Professional Documents
Culture Documents
Basic Pharmacokinetics
Michael C. Makoid, Ph.D.
Professor of Pharmaceutical Sciences
Creighton University School of Pharmacy
and Allied Health Sciences,
Omaha, Nebraska
Phillip J. Vuchetich
Pharm.D. Candidate
Creighton University School of Pharmacy
and Allied Health Sciences,
Omaha, Nebraska
Basic Pharmacokinetics
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ISBN 0-000-000000-0
ABCDEFGHIJ-DO-89
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Acknowledgement
When I first started teaching, I had the good fortune to work with another new
Ph.D., John Cobby. We struggled through our first five years on the otherside of
the podium together and learned many of the tenents upon which this book is
based, not content but process. First and formost, it was his belief that students are
bright, enthusiastic and hardworking. We should tell them what to do and get out
of their way. We both prepared extensive handouts complete with even more
extensive practice problems so that the student could experience the scientific
method as a detective might solve a murder mystery. The idea was to make learning pharmaceutical science interesting and fun. Through the years, as the methods
became more refined, student perceptions and performance improved dramatically.
John ultimately abandoned academe to go to work in the real world of industry,
clearly their gain and our loss. I approached him some years ago to co-author this
text. He declined believing himself to be too far removed from the cutting edge of
this discipline. That may be true (I doubt it!), but what can not be argued is that he
was a major contributor to this book in his philosophy and class notes. Over the
years, the explainations were rewritten and revised. Many new problems were
added and some were suplanted. These teaching aides have evolved but their origins are clear. Using the industry standard regarding authorship, which defines an
author as one whose contributions significantly alters the content of the paper, Dr.
Cobby is an author of this book.
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CHAPTER 1
Introduction
Basic Pharmacokinetics 1-2
Course Objectives: 1-3
Course Arrangement: 1-3
Learn the tools; get the pharmacokinetic parameters from patient information. 1-3
Learn the modifications of the pharmacokinetic parameters which result from illness. 1-5
Apply the tools; use the pharmacokinetic parameters to develop dosage regimens. 1-5
Apply the tools in specialized drug classes. 1-5
Exams
1-7
1-9
Tentative Schedule
1-17
Study Group 1: Learn the tools - obtain pharmacokinetic parameters from data. 1-17
Study group 2: Learn how the parameters are modified. 1-19
Study Group 3: Apply the tools in compromised patients. 1-20
Study Group 4: Apply the tools in special cases. 1-20
1-22
1-22
Pharmacokinetic Symbolism
1-25
CHAPTER 2
1-32
Mathematics Review
Concepts of Mathematics 2-2
Mathematical Preparation 2-3
Zero and Infinity 2-3
Expressing Large and Small Numbers 2-3
Significant Figures 2-4
Rules of Indices 2-4
Logarithms 2-6
Natural Logarithms 2-6
Negative Logarithms 2-9
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Calculus
2-14
Graphs
2-16
2-24
Pharmacokinetic Modeling
2-29
2-44
2-48
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CHAPTER 3
Pharmacological Response
Pharmacological Response
3-2
3-4
3-7
Problems
Answers:
Answers:
Answers:
CHAPTER 4
3-9
3-11
Oxpranolol 3-18
Minoxidil 3-21
Propranolol 3-23
4-2
Plasma 4-2
Iv bolus, parent compound, plasma Problems
Urine 4-47
Metabolite
4-7
4-51
Plasma 4-51
Urine 4-56
CHAPTER 5
I.V. Infusion
Parent compound
5-2
Plasma 5-2
Problems
5-10
CHAPTER 6
Biopharmaceutical Factors
CHAPTER 7
Oral Dosing
Oral dosing
7-3
CHAPTER 8
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8-2
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Bioequivalence
8-20
8-44
Summary
8-54
Questions 8-55
Answers to Questions
8-57
Bioavailibility Equations
Problems 8-60
Solutions 8-80
8-58
References
CHAPTER 9
8-103
Clearance
Equations 9-2
Definitions and Terms
9-3
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9-4
9-5
9-7
9-10
9-10
9-14
Problems
CHAPTER 10
9-17
10-2
10-4
CHAPTER 11
10-10
Multicompartment Modeling
Executive Summary 11-2
Equations 11-3
PHARMCOKINETICS: MAMMILLARY MODELS
Begin 11-90
Problems 11-91
11-4
CHAPTER 12
Protein Binding
CHAPTER 13
13-14
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Answers 13-14
CHAPTER 14
Nifedipine Data 3
Nifedipine Questions 4
Nifedipine Solutions 6
Enalapril - Section 1 11
enalapril data 11
Enalapril Questions 13
enalapril Solutions 14
Ciprofloxacin Section 1 19
Ciprofloxacin data 19
Ciprofloxacin Questions 20
Ciprofloxacin Solutions 21
Methylphenidate Section 1
23
methylphenidate data 23
MethylPhenidate Questions: 24
methylPhenidate Solutions 25
Adinazolam - Section 1
27
ADINAZOLAM DATA 27
Adinazolam Questions 28
Adinazolam Solutions 30
Labetalol - Section 1
32
labetalol data 32
labetalol Questions 33
labetalol Solutions 34
Zidovudine Section 1
36
zidovudine data 36
Zidovudine Questions 38
Zidovuldine Solutions 40
Fosinopril Section 1
42
fosinopril data 42
Fosinopril Questions 44
Fosinopril Solutions 46
Omeprazole
49
Omeprazole Data 49
Omeprazole Questions 50
Omeprazole solutions 53
57
EXP3312 DATA 57
EXP3312 & M1 Questions: 59
Graph Paper
CHAPTER 15
62
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Nifedipine Questions: 3
Valproate: Exam 2
Valproate Questions 7
Valproate Solutions 10
Methyl phenidate
11
Verapamil
15
Verapamil Questions 16
Verapamil Solutions 17
Hydromorphone hydrochloride
19
Fosinopril Sodium
23
Fosinopril Questions 24
Fosinopril Sodium Solutions
Remoxipride
26
28
Remoxipride Questions 29
Remoxipride Solutions 31
Naproxen
33
Naproxen Questions 34
Naproxen Solutions 36
38
CHAPTER 16
Exam 3
Pharmacokinetics Final Exam
16-2
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CHAPTER 1
Introduction
OBJECTIVES
At the completion of this chapter, the successful student shall be able to:
1.
define pharmacokinetics
2.
3.
4.
5.
6.
7.
8.
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Introduction
Pharmacokinetics is the mathematics of the time course of Absorption, Distribution, Metabolism, and Excretion (ADME) of drugs in the body. The biological,
physiological, and physicochemical factors which influence the transfer processes
of drugs in the body also influence the rate and extent of ADME of those drugs in
the body. In many cases, pharmacological action, as well as toxicological action, is
related to plasma concentration of drugs. Consequently, through the study of
pharmacokinetics, the pharmacist will be able to individualize therapy for the
patient.
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Introduction
Calculate (III) patient and drug specific pharmacokinetic parameters from patient data,
Predict (calculate - III) the changes in relevant pharmacokinetic parameters in the patient with
selected diseases,
Utilize the above parameters to individualize patient therapy (devise a dosage regimen - V),
Communicate his/her therapy recommendations to another competent health professional (write
a consult - V).
1.2.1
COURSE ARRANGEMENT:
Two courses are described below. The first, a two credit (Creighton University
required) and the second, a three credit (CU optional) version. The two credit
course will consist of major themes one through three and exams one and two,
while the three credit course will add theme four and exam three. The four major
themes are entitled:
Learn the tools; get the pharmacokinetic parameters from patient information.
Learn the modifications of the pharmacokinetic parameters which result from illness.
Apply the tools; use the pharmacokinetic parameters to predict patient response and develop
dosage regimens for the normal as well as for the compromised patient.
Each major theme of the course is further broken down into study sections, each
with their own set of general objectives as shown below:
1.2.2
1.
2.
3.
4.
Given a data set containing a pair of variables, the student will properly construct (III) various graphs of the data.
Given various graphical representations of data, the student will calculate (III) the slope
and intercept by hand as well as using linear regression.
The student shall be able to interpret (V) the meaning of the slope and intercept for the
various types of data sets.
The student shall demonstrate (III) the proper procedures of mathematical and algebraic
manipulations.
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Introduction
5.
The student shall demonstrate (III) the proper calculus procedures of integration and differentiation.
6. The student shall demonstrate (III) the proper use of computers in graphical simulations
and problem solving.
7. Given the assumptions for the model, the student will construct (III) models of the ADME
processes using Laplace Transforms.
8. The student shall develop (V) integrated equations associated with the above models.
9. The student shall generate a pharmacokinetic model based on given information.
10. The student shall interpret a given model mathematically.
11. The student shall predict changes in the final result based on changes in variables throughout the model.
2.
Given patient data of the following types, the student will be able to properly construct
(III) a graph and compute (III) the slope: response (R) vs. concentration (C), response (R)
vs. time (T), concentration (C) vs. time (T)
Given any two of the above data sets, the student will be able to compute (III) the slope of
the third.
2.
Given patient drug concentration and/or amount vs. time profiles, the student will calculate (III) the relevant pharmacokinetic parameters available ( V d , K, k m , k r , AUC , Clearance, MRT) from IV data.
Given the appropriate pharmacokinetic parameters, the student shall simulate (III)
I.V. bolus/infusion dosing for parent compounds
Plasma concentration vs. time profile analysis
3.
4.
5.
Given patient drug concentration and/or amount vs. Time profiles, the student will calculate (III) the relevant pharmacokinetic parameters ( V d , K, k m , k r , k a , AUC , Clearance,
MRT, MAT) available from oral data.
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F. Bioavailability objectives:
1.
Given sufficient data to compare an oral product with another oral product or an IV product, the student will estimate (III) the bioavailability (compare AUCs) and judge (VI) professional acceptance of the product with regard to bioequivalence (evaluate (VI) AUC, T p
and ( C p )max ).
2.
1.2.3
The student will write (V) a professional consult using the above calculations.
1.2.4
Given patient information regarding organ function, the student will calculate (III)
changes in clearance and other pharmacokinetic parameters inherent in compromised
patients.
1.2.5
Given population average patient data, the student will devise (V) dosage regimens which
will maintain plasma concentrations of drug within the therapeutic range.
Given specific patient information, the patient will justify (VI) dosage regimen recommendations.
Given patient information regarding organ function, the student will devise (V) and justify
(VI) dosage regimen recommendations for the compromised patient.
The student will write (V) a professional consult using the above calculations
Given patient Concentration and/or Amount of Drug vs. Time, profiles the student will
calculate (III) the relevant pharmacokinetic parameters( V d1 , Alpha, A 1 , Beta, B 1 ,
k 10 , k 12 , k 21 , AUC , Clearance, compartmental amount ratios) available from two com-
2.
3.
4.
5.
partment data.
Given population average patient data, the student will devise (V) a dosage regimen which
will maintain plasma concentrations of drug within the therapeutic range.
Given specific patient information, the patient will justify (VI) the optimal dosage regimen.
Given patient information regarding organ function, the student will devise (V) and justify
(VI) the optimal dosage regimen for the compromised patient.
The student will write (V) a professional consult using the above calculations.
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Introduction
Given population average patient data, the student will devise (V) dosage regimens which
will maintain plasma concentrations of unbound drug within the therapeutic range.
Given specific patient information, the patient will justify (VI) the optimal dosage regimen.
Given patient information regarding organ function, the student will devise (V) and justify
(VI) dosage regimens for the compromised patient.
The student will write (V) a professional consult using the above calculations.
Given population average patient data, the student will devise (V) a dosage regimen which
will maintain plasma concentrations of drug within the therapeutic range.
Given specific patient information, the patient will justify (VI) the optimal dosage regimen.
Given patient information regarding organ function, the student will devise (V) and justify
(VI) dosage regimens for the compromised patient.
The student will write (V) a professional consult using the above calculations.
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Introduction
1.3 Exams
How are the exams
made?
1.3.1
Exams will consist of problems which will be linked directly back to an objective
(above) and a library assignment in which you will be asked to evaluate a research
article with the tools available to you by the time of the exam as discussed below.
What do I have to do in
the library?
1.
2.
Given a suitable primary research article in the area of pharmacokinetics, the student shall
calculate the pharmacokinetic parameters from the data using the tools learned in class.
The student shall communicate in writing the results of such calculations with suitable
commentary regarding differences and interpretations.
1.
The problem sets show what data you need for each of these.
First Exam
What content should I
look for in the paper and
what is its relative
worth?
10 pts
12.5 pts
IV Infusion
12.5 pts
Pharmacological Response
15 pts
Second Exam
Oral Dosing / Bioavailability
10 pts
10 pts
12.5 pts
Dosage Regimen
15 pts
2.
10 pts
12.5 pts
15 pts
Include a Xerox copy of the entire paper. I need to evaluate it, too.
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Introduction
3.
Enlarge the graph by successive Xeroxes so that you can accurately evaluate the data.
4.
5.
6.
Comment on any differences of parameter calculation or interpretation. See
objectives above (Paragraph).
7.
Write an exam question to obtain pharmacokinetic parameters. You know
from the first exam what they should look like.
Why do I need to do this
library assignment?
Each of the above sections is designed to bring the student an understanding of the
information and the processes necessary to operate as a competent professional in
the area of pharmacokinetic evaluation and consulting. Consequently, the
course will evolve from a quantitative, manipulative mathematics course to a
course which stresses communication skills. Consults will be graded not only on
content (the proper dosage regimen for the patient) but also grammar, punctuation,
spelling, organization and neatness. You may have the best medical information in
the world, but if it is poorly executed, it will be ignored.
This course will probably be one of the more rigorous ones that you will have
experienced in your college career to date. It will be one of the first ones which
attempt to show some clinical relevance. The course can be successfully completed with your current skills and background. It is not difficult IF (and that is a
big IF) taken slowly, in small bites. Its just like eating an elephant - you can't do it
all in one sitting. Some of you may try to get it all the night before the exam,
regardless of my admonitions and those of your upper-class friends (ask them!). In
many cases, that has been more than sufficient to get A's and B's on exams in previous courses. Past experience tells many of you that you can do it. I suggest that
the requirements and expectations of a professional school are considerably more
than your undergraduate experience and it most likely will not work in many
courses which require assimilation of the information presented, as is expected in a
professional program.
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I.
To Know: means to memorize (recognize, recall) (Many college courses
require only this level of cognitive effort, hence the extensive experience with
multiple guess exams).
II.
To Comprehend: means to translate; to be able to put information into your
own words. (Essay exams routinely call for this level of effort on the part of the
student).
III.
To Apply: means to be able to use knowledge, rules and principles in an
unfamiliar situation. (This is the lowest level of skill necessary to function at a
technician level).
IV.
To Analyze: means to be able to critically examine a body of knowledge
and to be able to identify the relationships. (This is where a B.S. graduate should
operate. Education obviates the need for teachers.)
V.
To Synthesize: means to put together information, not necessarily previously so organized, in order to get a new piece of information. (This is the beginning level of professional judgment).
VI.
To Evaluate: means to be able to judge the worth of an idea, form hypotheses and do problem solving, research, invent new knowledge. (This is the doctoral
level of participation in the area).
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Introduction
1.
Provide individualized learning methods: Some students learn by hearing
and others by seeing (auditory or visual learners). I have designed the course to
accommodate both types of learners. In class, I will provide you with executive
summaries of what you read. I will provide group leaders with detailed reviews of
materials for which they are responsible. I will tell you what I'm going to say, say
it, and then tell you what I said. I will also attempt to write it out and draw appropriate graphs, charts and pictures as well as appropriate visual aids in class and
with the homework problems. I will provide you with ample examples of the types
of manipulations that you will be expected to do. I will provide you with ample
problem sets so that you may practice those manipulations. I will provide you
with computer simulations so that you may see these manipulations in action and
begin to get a feel for the numbers and their magnitude. Feedback and interaction
is encouraged. If I am not meeting your perceived needs, you must tell me. Some
students might feel too intimidated to ask questions. To obviate this problem, you
will elect a group team leader, an ombudsman, whose job it will be to carry your
questions, concerns, and comments to me. It is your job and his responsibility to
see that the group interaction facilitates the learning process. This is not to prevent
you coming to see me but offered as another avenue of communication.
2.
Provide clinical relevance to the practice of pharmacy. This will be stressed
at all times. I will also relate real clinical experiences; virtually all of the problems
come from real patients. Some educators believe examples must fit the theory
exactly. This gives the student a false set of reality parameters. Consequently,
when the data does not fall on the line the student rejects relevant information.
You will become familiar with real data, and the problems associated with real
data.
3.
Give adequate feedback: Evaluation of your performance will be available
to you at all times. A running evaluation, updated weekly will be on my door for
your review. You may check any thing with me at any time. I expect that you will
see me outside of class time either individually if you need help or in supervised
review sessions. You must see me for assistance if your performance is unsatisfactory.
4.
Teach: As an operational definition this means: clarifying what you read,
demonstrating how and why things work as they do, and unifying the material attempting to generate the A - HA! syndrome. The correlate of teach from the student view is learn. Neither is a passive process. I can not open your head and pour
the knowledge in. A saying in education is: Knowledge maketh a bloody
entrance. You must expend the effort necessary for you to learn.
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Introduction
5.
Facilitate Learning. You received objectives (above) and a summary for
each study section (chapters in this text), of exactly what is expected of you with
examples in the problem sets at the end of each chapter. We will have ample time
during class to field questions generated by the correlated reading and problem
sets, as well as homework assignments. I will not be duplicating any book's efforts.
Student participation in class is required. You will answer (as well as ask) questions, do problems in class. You will sound things out and get feedback from me
and your fellow colleagues. Remember - the class is to help you learn. It is not the
sole means of learning, nor am I the source of all knowledge. Its only reason for
being is to help you organize and summarize what you learn. It has a relatively
simple plan with multiple examples. From these examples you will develop concepts which will obviate the need for memorizing individual facts (or actually me
entirely). I will assist you in the formation of these concepts. It is patently obvious
that I can not give you every possible example of every type of question that you
will be asked during your professional career. For one thing I don't know what
questions you will be asked nor problems you will encounter. Going from the specific to the general forms concepts which will allow you to go from the general to
the specific, even if you have never been there before. The total medical knowledge is now doubling at a rate of every 4 years. I can not teach you the content necessary to operate 5 years in the future, let alone 40. You must learn to learn.
Hence, if you plan to become a competent professional, you must operate at least
in Bloom's level V.
6.
Be available: I do not have office hours. I believe them to be restrictive
from your view point. What I do have is a schedule prepared two weeks in advance
of when I am NOT available. You may set an appointment, at least a 1/2 day in
advance to guarantee that I see it, any other time. Of course, appointments are not
necessary if I'm in my office, but you take the chance of my not being there or
someone else being there ahead of you if you do not sign up. You may contact me
by e-mail: makoid@creighton.edu, or by phone: 402-280-2952.
7.
Be responsive: After each study section, you will be asked to provide me
with a one minute summary of the topic consisting answering the following questions:
a.
b.
What was clear about the study section? What was done well?
c.
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Introduction
After each exam, in addition to working out the problems, we will decide whether
any individual question was not covered by the objectives. Note: Not that it was
tough, not that you got it wrong, not that it didn't allow you to tell me what you
knew, but did I tell you that I was going to ask you to do it? (Was it covered by the
objectives?)
8) Evaluate your performance fairly and honestly: Quite simply, I'm going to tell
you what I expect that you will do. I will show you how to do it. I will provide you
with practice in doing it. I will provide you with an exam which tests your ability
to do it. The exams, as well as the whole course, will use real data and/or pharmacokinetic parameters for real drugs in real patient settings, much like the state
board exams (and hopefully real life). Like both of these situations, all answers are
interconnected. What that means is, if you improperly calculate a parameter which
is needed to make another calculation which is used to make a third, etc. ALL are
wrong. Conversely, if you can't get a particular calculation by one method or equation, try another. That's simply the way it is. You probably wouldn't get much sympathy if you calculated a dosage regimen properly based on a wrong elimination
rate constant and ended up killing your patient.
You Will:
1) Come prepared to participate in class. This is your full time job. If you are
working full time, it is usually 40 to 60 hours per week. If you go to college 15 to
18 credits and prepare/study 2 hours for each credit, you work 45 to 55 hour per
week - you have a full time job. Your commitment is the 45 to 50 hour week not
just the contact hours and a night for each exam. This specifically means for each 1
hour class, I expect no less than 2 hours of preparation on your part. Each of you
will be assigned to a study group. You will work the problems together and teach
each other both in and out of class. We will have group discussion of class as well
as group problem solving. It will be your responsibility that every member of
your group be adequately prepared to answer for the group during recitation. There
will be a grade for group participation. Part of your grade will be based on quizzes,
how well your group performed both on the material for which you were responsible as well as overall and your peer evaluation.
2) Read the text. When you read, read critically. Do you understand each idea?
Place a <+> (in pencil) in the left side of each paragraph after you read and understand it. If you don't get it, place a <?> and come prepared to ask about it in class.
3) Work the problems. Check the answers. These come from old exams, so they
are the type that you are likely to see. Work them in your study groups so that
everyone can see your thought processes. Bring them to class if you can not do
them or come and see me privately. Be prepared to show me your attempts at solving the problem. I will show you how to get started and give direction to your
thought. I will not work the problem for you. You would not learn if I did it for
you. It is crucial that you work the problems. Each has a specific objective. Over-
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Introduction
all, they contribute to your gaining facility in the processes that a pharmacokineticist must know how to do.
Can I just coast
through?
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Introduction
Programs that are currently being used in the course are The Scientist and PKAnalyst both from MicroMath Scientific Software, P.O. Box 71550, Salt Lake City, UT
84171-0550; or http://www.micromath.com. A working student version of the software is available free for the downloading for your own work at home. A full
working version is on the Pharmacy Server.
In addition to the above course objectives, there are specific objectives for the use
of computers in the course. They are:
1.
Simulation. The student will construct a graph of the drug time course
using classical pharmacokinetics. The student will demonstrate effects of changes
in pharmacokinetic parameters on the ADME processes and correlated pharmacological / therapeutic response.
2.
The student shall statistically evaluate models with regard to fit of data
using both linear and nonlinear regression analysis. The student will calculate
pharmacokinetic parameters which best describe the processes of ADME.
These objectives will be met in a variety of ways. Clearly, the most direct method
is the solution of the problem sets by computer. First, I expect that you would do
the problem by hand, complete with graphs and other supporting calculations followed by computer simulation and data analysis. Just how close did you come to
the best fit? Next, a portion of each exam will be a library exercise in which you
will find and evaluate a published article according to the principles that you
learned in class utilizing the computer facilities. How close did you come the
authors numbers? Do you, in fact, even agree with the authors? You will prepare a
short consult in which you describe the patient and what the authors did along with
your support (or non-support) of the authors conclusions.
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Introduction
1.
You will need a good calculator - One with
have it ASAP. You will use it in class.
and
ln x
2.
You will also need 2 cycle semilog paper and a clear straight edge ruler for
use in class. These are available in the book store or at an office supply store.
3.
You will need access to a computer (486 DX or higher). Micromath has
made available a student version of the programs for a nominal fee (This software
is pre-loaded in the Criss computer lab; you may purchase a copy for home use)
4.
You will need a 3 D three-ring binder for collecting and maintaining all
the pages in this book as well as your class notes.
What do I need to do in
and out of class?
Work in your study groups. You never learn it so well as when you teach it to
someone else. Everyone benefits from a well run prepared study group. You are
not in competition with your fellow classmates. If everyone earns an A, then
everyone will receive one.
Organize and label your study notes. This is basic survival. This is one strategy
that I find works well. I recommend it highly. Good study notes are formatted on
loose-leaf in a three ring binder. The individual pages have a line drawn down
about 1/3 the way in. The notes are taken on the right (2/3) of the page, while
labels go in the left. The labels on the left are often written as questions, which are
answered in the text on the right. Loose leaf binders allow for the incorporation of
reading summaries as well as relevant problems and homework to be organized
with a divider all in one place. You should write intelligently, with proper punctuation and spelling as if you were preparing a consult for a physician. Organization is
the key.
Remember: you may have all the information in the world at your fingertips; be
able to solve the most difficult therapy problem and no one will listen to you if you
can't communicate intelligently. Chapters in the book will be organized as above.
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Introduction
1.7.2
1.
At the lowest level, a decent grade for a significant course. Specific grades
will be earned by attaining the following averages:
A 90 and above
B+ 85 to 89
B 80 to 84
C+ 75 to 79
C 70 to 74
D 60 to 69
F 59 and below
4
You will learn to learn. There is an old proverb which goes: Give a man a
fish and you feed him for a day. Teach a man to fish and you feed him for a lifetime. The B.S. Degree is designed to eliminate teachers. An educated man is one
who has learned to how to learn, not one who memorized a page in a book. That
is what you need to be a professional. The total medical knowledge is doubling at a
rate of every 3-4 years. That means that you will be out of date shortly after graduation (if not before) if you simply memorized content and don't learn to learn and
continue to learn throughout your career.
One last piece of information: Neither you nor I will not tolerate any academic
misconduct. Anyone caught will minimally receive an F for their efforts and I
will recommend dismissal from the program. The profession has no room for
unprofessional behavior. I will prosecute.
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Introduction
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Introduction
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Rate vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
F: I.V. infusion
1. Parent compound
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
e. Professional communication.
1. Metabolite
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
e. Professional communication.
End of Material for first exam (six weeks for semester, two weeks for summer session)
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Introduction
1.8.2
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Introduction
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
e. Professional communication.
I: Bioavailability, Bioequivalence, Drug product selection
1. Relative and Absolute Bioavailability
2. Factors Influencing Bioavailability
3. Methods of Assessing Bioavailability
I. in vivo
II. in vitro
III. Correlation
4. Bioequivalence
5. Bioavailability
6. Drug Product Selection
1.8.3
1.8.4
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Introduction
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Introduction
1.9.1
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Introduction
1.1.4 Identify patient factors, biosocial factors, and concurrent drug therapy that
are relevant to the maintenance of wellness and the prevention or treatment of a
disease or medical condition.
1.2.0 Assure the appropriateness of the patient's specific pharmacotherapeutic
agents, dosing regimens, dosage forms, routes of administration, and delivery systems.
1.2.1 Identify drug products by their generic, trade, and/or common names.
1.2.3 Evaluate drug therapy for the presence of pharmacotherapeutic duplications
and interactions.
1.2.5 Identify physicochemical properties of drug substances that affect their solubility, pharmacokinetics, pharmacologic actions, and stability.
1.2.6 Interpret and apply pharmacokinetic principles to calculate and determine
appropriate drug dosing regimens.
1.2.7 Interpret and apply biopharmaceutic principles and the pharmaceutical characteristics of drug dosage forms and delivery systems, to assure bioavailability and
enhance patient compliance.
1.3.0 Monitor the patient and/or patient information and manage the drug regimen
to promote health and assure safe and effective pharmacotherapy.
1.3.2 Evaluate patient information to determine the safety and effectiveness of
pharmacotherapy.
1.3.5 Identify and remedy interactions or contraindications with diagnostic or
monitoring tests or procedures.
Area 2: Assure the Safe and Accurate Preparation and Dispensing of Medications (Approximately 25% of Test)
2.1.0 Perform calculations required to compound, dispense, and administer medication.
2.1.1 Calculate the quantity of medication to be compounded or dispensed; reduce
and enlarge formulation quantities and calculate the quantity or ingredients needed
to compound the proper amount of the preparation.
2.1.3 Calculate the rate of drug administration.
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Introduction
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Introduction
1.10.1
DL
loading dose
Xa
Xm
Xu
X mu
X eff minimum amount of unchanged drug in body necessary for pharmacological response
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Introduction
1.10.2
Cp
Cm
KA
KM
KR
1.10.3
Vm
Vw
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Introduction
1.10.4
1.10.5
t'
t0
lag time
t 0.5
t max
t dur
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Introduction
1.10.6
1.10.7
k mu
k ij
k0
Cl r
Cl m
Cl cr
creatinine clearance
Cl H
X
---t
RH
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Introduction
1.10.8
Rr
VM
OTHER TERMS
AUC area under the plasma concentration-time curve (units: time * mass/volume)
AUMC area under the first moment of the plasma concentration-time curve (units:
2
time )
time )
time )
EH
Er
FRE
accumulation factor
intercept
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Introduction
1.10.9
f ss
fraction of steady-state
number of doses
Laplace operator
[ ]
SUBSCRIPTS
0
at time zero
at time infinity
ss
during steady-state
at time t
at time T
following dose n
diff
int
intrinsic
1.10.10 SUPERSCRIPTS
x
extrapolated
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Introduction
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Introduction
1 1
1 1
2
2
1
ln lim ( [ x ] [ x ] )! + --- + ( sin q ) + ( cos q ) =
cosh p 1 ( tanh p )
------------------------------------------------n
2
(EQ 1-2)
n=0
given that 100% bioavailability of a single I.V. bolus dose is equal to 1, and both
doses contain an equal mass of active drug.
For the struggling pharmacokinetics student, we would like to show the veracity of
this statement. Of course, it is obvious that; the reverse of the transpose is equal to
the transpose of the inverse in matrix theory. i.e.:
1 1
[x ]
1 1
= [x ]
(EQ 1-3)
(EQ 1-4)
Consequently,
1 1
([x ]
1 1
[ x ] )! = 1
(EQ 1-5)
2
2
1
ln lim 1 + --- + ( sin q ) + ( cos q ) =
(EQ 1-6)
By definition,
e = 1 + 1---
(EQ 1-7)
and
1 = cosh p 1 ( tanh p )
(EQ 1-8)
Thus:
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Introduction
----n-
ln e + ( sin q ) + ( cos q ) =
(EQ 1-9)
n = 02
Also,
2 =
----n1
(EQ 1-10)
n = 02
and
1 = ln e
(EQ 1-11)
and
2
1 = ( sin q ) + ( cos q )
(EQ 1-12)
(EQ 1-13)
under the stated conditions, two I.V. bolus doses given simultaneously will have
twice as much available drug as a single I.V. bolus dose.
You will agree, however, equation 1-1 is obvious and therefore is more easily
understood by a pharmacokineticist!
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CHAPTER 2
Mathematics Review
Given a data set containing a pair of variables, the student will properly construct
(III) various graphs of the data.
2.
Given various graphical representations of data, the student will calculate (III) the
slope and intercept by hand as well as using linear regression.
3.
The student shall be able to interpret (V) the meaning of the slope and intercept
for the various types of data sets.
4.
The student shall demonstrate (III) the proper procedures of mathematical and
algebraic manipulations.
5.
The student shall demonstrate (III) the proper calculus procedures of integration
and differentiation.
6.
The student shall demonstrate (III) the proper use of computers in graphical simulations and problem solving.
7.
Given information regarding the drug and the pharmacokinetic assumptions for
the model, the student will construct (III) models and develop (V) equations of the
ADME processes using LaPlace Transforms.
8.
9.
The student will predict (IV) changes in the final result based on changes in variables throughout the model.
10.
The student will correlate (V) the graphs of the data with the equations and models so generated.
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Mathematics Review
This chapter is meant to review the concepts in mathematics essential for understanding kinetics. These concepts are generally taught in other mathematical
courses from algebra through calculus. For this reason, this chapter is presented as
a review rather than new material. For a more thorough discussion of any particular concept, refer to a college algebra or calculus text.
Included in this section are discussions of algebraic concepts, integration/differentiation, graphical analysis, linear regression, non-linear regression and the LaPlace
transform. The Scientist and PKAnalyst are the computer programs used in this
course.
A critical concept introduced in this chapter is the LaPlace transform. The LaPlace
transform is used to quickly solve (integrate) ordinary, linear differential equations. The Scientist by Micromath Scientific Software, Inc.1 is available for working with the LaPlace transform for problems throughout the book.
1. MicroMath Scientific Software, Inc., P.O. Box 21550, Salt Lake City, UT 84121-0550,
http://www.micromath.com
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Mathematics Review
2.2.2
Examples:
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Mathematics Review
2.2.3
SIGNIFICANT FIGURES
A significant figure is any digit used to represent a magnitude or quantity in the
place in which it stands. The digit may be zero (0) or any digit between 1 and 9.
For example:
TABLE 2-1. Significant
Value
Figures
Significant
Figures
Number of
Significant
Figures
(a)
572
2,5,7
(b)
37.10
0,1,3,7
(c)
10.65 x 104
0,1,6,5
(d)
0.693
3,6,9
(e)
0.0025
2,5
Examples (c) to (e) illustrate the exceptions to the above general rule. The value 10
raised to any power, as in example (c), does not contain any significant figures;
hence in the example the four significant figures arise only from the 10.65. If one
or more zeros immediately follow a decimal point, as in example (e), these zeros
simply serve to locate the decimal point and are therefore not significant figures.
The use of a single zero preceding the decimal point, as in examples (d) and (e), is
a commendable practice which also serves to locate the decimal point; this zero is
therefore not a significant figure.
Significant figures are used to indicate the precision of a value. For instance, a
value recorded to three significant figures (e.g., 0.0602) implies that one can reliably predict the value to 1 part in 999. This means that values of 0.0601, 0.0602,
and 0.0603 are measurably different. If these three values cannot be distinguished,
they should all be recorded to only two significant figures (0.060), a precision of 1
part in 99.
After performing calculations, always round off your result to the number of significant figures that fairly represent its precision. Stating the result to more significant figures than you can justify is misleading, at the very least!
2.2.4
RULES OF INDICES
What is an index?
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Sometimes n is referred to as the exponent, giving rise to the general term, Rules
of Exponents. There are three general rules which apply when indices are used.
(a) Multiplication
n
A A = A
A B
n+m
n
n+m
= A
--- B
B
(b) Division
n
A - = An m
-----m
A
n
A - = A
n Bn m
------- B
m
B
(c) Raising to a Power
n m
(A )
= A
nm
A =
A = 1
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Mathematics Review
2.2.5
LOGARITHMS
What is a logarithm?
Some bodily processes, such as the glomerular filtration of drugs by the kidney,
are logarithmic in nature. Logarithms are simply a way of succinctly expressing a
number in scientific notation.
In general terms, if a number (A) is given by
A = 10
then
log ( A ) = n
where log signifies a logarithm to the base 10, and n is the value of the logarithm
of (A).
5
0.85
0.85
10 = 10
( 5 + 0.85 )
= 10
5.85
2.2.6
The number before the decimal point is called the characteristic and tells the placement of the decimal point (to the right if positive and to the left if negative). The
number after the decimal is the mantissa and is the logarithm of the string of numbers discounting the decimal place.
NATURAL LOGARITHMS
Instead of using 10 as a basis for logarithms, a natural base (e) is used. This natural
base is a fundamental property of any process, such as the glomerular filtration of a
drug, which proceeds at a rate controlled by the quantity of material yet to undergo
the process, such as drug in the blood. To eight significant figures, the value of the
transcendental function, e, is
e = 2.7182818 ....
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Mathematics Review
Strictly speaking,
e = 1+
---x!
1
x=1
x=1
= e
n+m
By definition,
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ln ( NM ) = n + m ;
but
n = ln ( N )
and
m = ln ( M ) ,
hence
ln ( NM ) = ln ( N ) + ln ( M )
Thus, to multiply two numbers (N and M) we take the natural logarithms of each,
add them together, and then take the anti-logarithm (the exponent, in this case) of
the sum.
(b) Division
N- = ln ( N ) ln ( M )
ln ---M
(c) Number Raised to a Power
m
ln ( N ) = m ln ( N )
There are three noteworthy relationships involving logarithms:
(i) Number Raised to a Negative Power
ln ( N
1-
) = m ln ( N ) = m ln --N
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Mathematics Review
ln ( m
--m
1
N ) = ln N = ---- ln ( N )
m
2.2.7
NEGATIVE LOGARITHMS
The number 0.00713 may be expressed as:
3
7.13 10 , or
10
10
0.85
10 , or
2.15
Hence, log ( 0.00713 ) = 2.15 , which is the result generated by most calculators.
However, another representation of a negative logarithm (generally used by referencing a log table):
log (0.00713) = 3.85
The 3 prior to the decimal point is known as the characteristic of the logarithm; it
can be negative (as in this case) or positive, but is never found in logarithmic
tables. The .85 following the decimal point is known as the mantissa of the logarithm; it is always positive, and is found in logarithmic tables.
In fact 3 is a symbolic way of writing minus 3 (-3) for the characteristic. In every
case the algebraic sum of the characteristic and the mantissa gives the correct
value for the logarithm.
Example: log (0.00713) = 3.85
Add -3 and 0.85
Result is -2.15, which is the value of log ( 0.00713 )
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Mathematics Review
The reason for this symbolism is that only positive mantissa can be read from antilogarithmic tables, and hence a positive mantissa must be the end result of any logarithmic manipulations. Note that while there are negative logarithms (when N <
1), they do not indicate that number itself is negative; the sign of a number (e.g., N) is determined only by inspection following the taking of anti-logarithms.
2.2.8
62.54 = 6.254 10
Hence, 6.254 10 = 10
0.7962
10 = 10
1.7962
0.00329 = 3.29 10
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Mathematics Review
(d) We wish to find anti-log (1.3134) Look up the anti-log for the 0.3134 (mantissa) in a table: it is 2058.
1
2.2.9
DIMENSIONS
What is a unit?
There are three fundamental dimensions which are used in various combinations to
express the properties of matter. Each of these dimensions has been assigned a definite basic unit, which acts as a reference standard.
TABLE 2-2 Dimensions
Dimension
Dimensional
Symbol
Unit
Unit Symbol
Length
meter
Mass
gram
Time
second
sec
In the metric system, which emerged from the French Revolution around 1799,
there are various prefixes which precede the basic units and any derived units. The
prefixes indicate the factor by which the unit is multiplied. When the index of the
factor is positive the prefixes are Greek and have hard, consonant sounds. In contrast, when the index is negative, the prefixes are Latin and have soft, liquid
sounds. (see Table 2-3).
Examples: An average adult male patient is assumed to have a mass of 70 kilograms (70 kg). An average adult male patient is assumed to have a height of 180
centimeters (180 cm). A newly minted nickel has a mass of 5.000 g. Doses of
drugs are in the mg (10-3 g) range (occasionally g) never Kg (103 g) or larger. Students have told me that the dose that they have calculated for their patient is 108 g
(converting to common system - ~ 100 tons). I doubt it. Get familiar with this system. Note that the plural of Kg or cm is Kg or cm; do not add an s. In pharmacy
there are two derived units which are commonly used, even though they are
related to basic units. The Liter (L) is the volume measurement and is a cube 10
cm on a side (1L = (10cm)3 = 1000 cm3 ) while the concentration measurement
and has the units of Mass per Volume.
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Name
Symbol
exa-
peta-
tera-
giga-
mega-
kilo-
hecto-
deca-
da
Name
Symbol
18
deci-
15
centi-
12
milli-
micro-
nano-
pico-
femto-
atto-
10
10
10
10
10
Multiplication Factor
10
10
10
10
10
10
10
10
1
2
3
6
9
12
15
18
TABLE 2-4
2.2.10
Dimension
Dimensional
Symbol
Volume
liter
Concentration
grams/liter
g/l
Unit
Unit
Symbol
DIMENSIONAL ANALYSIS
It is a general rule that the net dimensions (and units) on the two sides of any equation should be equal. If this is not so, the equation is necessarily meaningless.
Consider the following equation which defines the average concentration of a drug
FDin blood after many repeated doses, ( C b ) = ---------VK
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Mathematics Review
Where:
),
Writing the dimensions relating to the properties of the right-hand side of the equation gives:
M
M
------------------------ = ----1
V
VT T
Thus ( C b ) has the dimensions of M
----- , which are correctly those of concentration.
V
Sometimes dimensional analysis can assist an investigator in proposing equations
which relate several properties one with the other. If the units cancel, and you end
up with the correct unit of measure, you probably did it right. If you obtain units
that do not make sense, its guaranteed sure that you did it wrong.
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Mathematics Review
2.3 Calculus
What is Calculus?
Calculus concerns either the rate of change of one property with another (differential calculus), such as the rate of change of drug concentrations in the blood with
time since administration, or the summation of infinitesimally small changes (integral calculus), such as the summation of changing drug concentrations to yield an
assessment of bioavailability. In this discussion a few general concepts will be provided, and it is suggested an understanding of graphical methods should precede
this discussion.
2.3.1
DIFFERENTIAL CALCULUS
2.3.2
NON-LINEAR GRAPHS
Consider the following relationship: y = x
TABLE 2-5 x,
y sample data
27
64
As can be seen from the graph (Figure 2-1), a non-linear plot is produced, as
expected.
FIGURE 0-1.
y=x3
70
60
50
40
30
20
10
0
1
(Question: How could the above data be modified to give a linear graph?)
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Mathematics Review
2.3.3
2.3.4
We need to find the value of the slope of the line y = x when x = 2 (See Figure
1). Hence, we may choose incremental changes in x which are located around
x 2.
FIGURE 0-2. y / x
when x 2
x1
x2
y1
y2
y
-----x
64
64
16.000
27
26
13.000
1.5
2.5
1.0
3.375
15.625
12.250
12.250
1.8
2.2
0.4
5.832
10.648
4.816
12.040
1.9
2.1
0.2
6.859
9.261
2.042
12.010
1.95
2.05
0.1
7.415
8.615
1.200
12.003
-----y-
x
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Mathematics Review
Calculus deals with infinitesimally small changes. When the value of x is infinitesimally small it is written dx and is known as the derivative of x. Hence,
dy
------ = f ( x )
dx
Where dy/dx is the derivative of y with respect to x and f ( x ) indicates some function of x.
2.3.5
(EQ 1-14)
Multiplying out:
3
y + dy = x + 3x ( dx) + 3x ( dx ) + ( dx )
(EQ 1-15)
(c) The change in y is obtained by subtraction of the original expression from the
last expression. (i.e., Eq. 2 - Eq. 1)
2
dy = 3x ( dx ) + 3x ( dx ) + ( dx )
(EQ 1-16)
When dx is infinitesimally small, its magnitude tends to zero ( dx 0 ) . The limiting value of this tendency must be dx = 0 . At this limit,
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Mathematics Review
2
dy
------ = 3x
dx
(EQ 1-17)
2.3.6
RULE OF DIFFERENTIATION
Although the rate of change of one value with respect to another may be calculated
as above, there is a general rule for obtaining a derivative.
Let x be the independent variable value, y be the dependent variable value, A be a
constant, and n be an exponential power.
The general rule is:
If y = Ax
then
n1
dy
------ = nAx
dx
The Rules of Indices may need to be used to obtain expressions in the form
y = Ax
(e.g., if y =
2.3.7
x)
(a) If y = Ax ,
then y = A (i.e., y is constant)
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dy
Hence, ------ = 0
dx
Thus the derivative of a constant is always zero.
(b) Accept that if y = ln ( x )
dy
1
then ------ = --- .
dx
x
This derivative is important when considering apparent first-order processes, of
which many bodily processes (e.g., excretion of drugs) are examples.
(c) Accept that if y = Be
Ax
dy
base then ------ = ABe
dx
Ax
This derivative will be useful in pharmacokinetics for finding the maximum and
minimum concentrations of drug in the blood following oral dosing.
2.3.8
A SEEMING ANOMALY
Consider the following two expressions:
n
(a) If y = Ax , then
n1
dy
------ = nAx
dx
n
(b) If y = Ax + A ,
n1
n1
dy
+ 0 = nAx
then ------ = nAx
dx
Both of the original expressions, although different, have the same derivative. This
fact is recognized later when dealing with integral calculus.
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2.3.9
INTEGRAL CALCULUS
Generally integral calculus is the reverse of differential calculus. As such it is used
to sum all the infinitesimally small units (dy) into the whole value (y).
Thus,
dy
2.3.10
= y , where
RULE OF INTEGRATION
The derivative expression may be written:
n
dy
------ = Ax , or
dx
n
dy = Ax dx
To integrate,
y =
dy
Ax
dx = A x dx
n
Ax - + A
A x dx = --------------n+1
Where A is the constant of integration However, there is one exception - the rule
is not applicable if n = 1
2
Example: If dy
------ = 3x (See section 2.3.5),
dx
2+1
then y = 3x
--------------- + A , and
2+1
3
y = x +A
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2.3.11
y = x + A , therefore
3
0 = 0 + A , thus A = 0
In some examples, such as first-order reaction rate kinetics, the value of A is not
zero.
2.3.12
Upon integration, y = A ln ( x ) + A
This is the reverse of the derivative stated in section 2.3.10 (b).
2.3.13
A USEFUL INTEGRAL
Accept that if,
Ax
dy
------ = Be
dx
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then,
Ax
Be + A
y = ----------A
This integral will be useful for equations which define the bioavailability of a drug
product.
2.3.14
EXAMPLE CALCULATIONS
(a) Consider,
2
c = 3t ( t 2 ) + 5
Where c is the drug concentration in a dissolution fluid at time t .
Then, multiplying out,
3
c = 3t 6t + 5
The rate of dissolution at time t is
2
dc
------ = 9t 12t
dt
Then rearranging,
2
dc = 9t dt 12t dt
The integral of c is:
c =
dc
= 3t + A 6t + B
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c = 3t = 6t + D
where D = A + B
We know, from previous work, that when t = 0 , then c = 5
Substituting 5 = D , the final expression becomes:
2
c = 3t + 6t + 5
Which is the initial expression in example (a) above.
(c) Following administration of a drug as an intravenous injection,
dC p
------------- = KC p
dt
Where C p is the plasma concentration of a drug at time t
K is the apparent first-order rate constant of elimination.
Rearranging,
1- dC
K dt = ----p
Cp
Kt = K dt =
- dC p
----Cp
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Substituting, 0 = ln ( C p )0 + A
Or,
A = ln ( C p )0
Hence
Kt = ln ( C p ) ln ( C p ) 0
or,
ln ( C p ) = ln ( C p ) 0 Kt
or,
Cp = ( C p )0 e
Kt
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2.4 Graphs
Why do we graph?
We would like to agonize the chaotic world around us so that we can predict (see
into the future) and retrodict (see into the past) what will happen or has happened.
Our recorded observations are collectively known as data. We make a theory
about what we think is happening and that theory is expressed in an equation. That
determines our paradigm of how we see the world. This paradigm is expressed as
a graph. The language of science is mathematics and graphs are its pictures.
TABLE 2-6
English
What is a graph?
Science
Observations
Data
Theory
Equations
Paradigms (pictures)
Graphs
A graph is simply a visual representation showing how one variable changes with
alteration of another variable. The simplest way to represent this relationship
between variables is to draw a picture. This pictorializing also is the simplest way
for the human mind to correlate, remember, interpolate and extrapolate perfect
data. An additional advantage is it enables the experimenter to average out small
deviations in experimental results (non-perfect, real data) from perfect data. For
example:
TABLE 2-7 Perfect
Perfect
Real
-3
-5
-4.6
-2
-3
-3.4
-1
-1
-0.6
+1
+0.8
+1
+3
+3.4
+2
+5
+4.4
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FIGURE 0-3.
-2
-4
-6
-3
-2
-1
Simply looking at the columns x and y (real) it might be difficult to see the relationship between the two variables. But looking at the graph, the relationship
becomes apparent. Thus, the graph is a great aid to clear thinking. For every graph
relating variables, there is an equation and, conversely for every equation there is a
graph. The plotting of graphs is comparatively simple. The reverse process of finding an equation to fit a graph drawn from experimental data is more difficult,
except in the case of straight lines.
2.4.1
GRAPHICAL CONVENTIONS
Certain conventions have been adopted to make the process of rendering a data set
to a graphical representation extremely simple.
The y variable, known as the dependent variable, is depicted on the vertical axis
(ordinate); and the x variable, known as the independent variable, is depicted on
the horizontal axis (abscissa). It is said that y varies with respect to x and not
x varies with y.
A decision as to which of the two related variables is dependent can only be made
be considering the nature of the experiment. To illustrate, the plasma concentration
of a drug given by IV bolus depends on time. Time does not depend on the plasma
concentration. Consequently, plasma concentration would be depicted on the y
axis and time on the x axis.
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Any point in the defined space of the graph has a unique set of coordinates: 1) the
x value which is the distance along the x axis out from the y axis and always
comes first; and 2) the y value which is the distance, along the y axis up or
down from the x axis, and always comes second. Several points are shown in
Figure 2. For example, (0,1) is on the line and (1,0) is not.
The intersection of x and y axis is the origin with the coordinates of (0,0). In two
dimensional spaces, the graph is divided into 4 quadrants from (0,0), numbered
with Roman numerals from I through IV. It should be readily apparent that the
coordinates for all points within a particular quadrant are of the same sign type i.e.,
TABLE 2-8 Quadrants
on a cartesian graph
2.4.2
A graph is a straight line (linear) only if the equation from which it is derived has
the form
y = mx + b
Where:
y = dependent variable
x = independent variable
m = slope of the straight line =
y
-----x
mx
is not linear
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However.
ln y = ln b + mx
is of the same general form as:
y = b + mx
and consequently a plot of ln y (the dependent variable) versus x (the independent variable) will yield a straight line with a slope of m and an intercept of ln b .
Expressions of any other form are non linear. For example:
An expression relating the plasma concentration of a drug ( C p ) over time ( t ) .
C p = C p0 e
Kt
( n m)
+ k2 x
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(n m + 1)
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where n 2 ;n = m + 1
or
K a FD
K t
Kt
C p = ------------------------ (e e a )
V ( Ka K )
(It is possible to resolve this equation into the summation of two linear graphs
which will be shown subsequently.)
2.4.3
From the equation a prediction may be made as to whether the slope is positive or
negative. In the previous example, the slope is negative, i.e: m = K
TABLE 2-9 Sample
t (min)
g-
C p ------ mL
ln C p
12
3.75
1.322
40
2.80
1.030
65
2.12
0.751
90
1.55
0.438
125
1.23
0.207
173
0.72
-0.329
The differences in both the y-values and the x-values may be measured graphically
to obtain the value of the slope, m. Then knowing the value of m, the value of K
may be found.
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FIGURE 0-4.
Plasma Concentration
Caffeine Concentration (
g/mL)
u
101
2.4.4
100
10-1
0
50
100
150
200
Time (min)
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TABLE 2-10
XY
12
1.322
144
15.864
40
1.030
1600
41.2
65
0.751
4225
48.815
90
0.438
8100
39.42
125
0.207
15625
25.875
173
-0.329
29929
-56.917
X = 505
Y = 3.239
X = 59623
XY = 114.257
( X ) = 255025
x
x = ------ = 4.167
n
y
y = ------ = 0.5398
n
Using the data from table 2-10 in the equation for the slope of the line
Cpo = e = e
1.4229
the anti-ln of
= 4.15
It is important to realize that you may not simply take any two data pairs in the
data set to get the slope. In the above data, if we simply took two successive data
pairs from the six data pairs in the set, this would result in five different slopes
( x y ) ranging from -0.0066 to -0.0125 as shown in table 2-11. Clearly, this is
unacceptable. Even to guess, you must plot the data, eyeball the best fit line by
placing your clear straight edge through the points so that it is as close to the data
as possible and look to make sure that there are an equal number of points above
the line as below. Then take the data pairs from the line, not the data set.
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2.4.5
Time (x)
ln Conc. (y)
y
-----x
12
1.322
-28
0.292
-0.0104
40
1.030
-25
0.28
-0.0112
65
0.751
-25
0.312
-0.0125
90
0.438
-35
0.231
-0.0066
125
0.207
-48
0.536
-0.0112
173
-0.329
PARALLEL LINES
Two straight lines are parallel if they have the same slope.
Calculating for the intercept of a linear graph (b):
(a) Not knowing the value of m;
The graph may be extrapolated, or calculations performed, at the situation where
t = 0 . In this case b = ln C p0 .
(b) Knowing the value of m;
There are two ways: for any point on the graph:
y 1 = mx 1 + b
b = y 1 mx 1
Hence, b may be calculated from a knowledge of y 1 and x 1 . Secondly, the graph
may be extrapolated or calculations performed, at the situation where t = 0 . In
this case,
b = ln C p
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2.4.6
GRAPHICAL EXTRAPOLATIONS
2.4.7
By using all the experimental data points, calculations may be made to find the
optimum values of the slope m, and the intercept, b. From these values the correlation coefficient (r).and the t-value may be obtained to indicate the significance.
Exact details of the theory are available in any statistical book, and the calculations
may most easily be performed by a computer using The Scientist or PKAnalyst in
this course.
The advantage of computer calculation is that it gives the one and only best fit to
the points, and eliminates subjective fitting of a line to the data.
2.4.8
GRAPHICAL HONESTY
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2.4.9
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0
10
10
10
8
6
4
2
0
For example (shown in Figure 0-5), these two parabolic curves represent the same
equation the only difference is the scales are different along the y axis.
Frequently it is not convenient to have the origin of the graph coincide with the
lower left hand corner of the coordinate paper. Full utilization of the paper with
suitable intervals is the one criteria for deciding how to plot a curve from the
experimental data. For example, the curve below (Figure 0-6) is poorly planned,
where the following (Figure 0-7) is a better way of representing the gas law
PV = nRT
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FIGURE 0-6.
50
40
30
20
10
0
0
FIGURE 0-7.
12
16
20
25
20
15
10
5
0
1
9 10
Pressure (atm)
2.4.10
2.4.11
SEMILOGARITHMIC COORDINATES
Exponential or logarithmic equations are very common in physical chemical phenomenon. One of the best ways of determining whether or not a given set of phenomenon can be expressed by a logarithmic or exponential equation is to plot the
logarithm of one property against another property. Frequently a straight line is
obtained and its equation can be readily found. For example:
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concentration of cyclosporine
Concentration
Time (hours)
0.25
1900
.75
1500
1.5
1300
900
600
390
ng
-----ml
These can be illustrated in three different ways (Figures 0-8, 0-9, 0-10),
A. Concentration vs. time directly
B. Log concentration vs. time directly
C. Log concentration vs. time with concentration plotted directly on to logarithmic
scale of ordinates.
FIGURE 0-8.
2000
1800
1600
1400
1200
1000
800
600
400
200
0
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FIGURE 0-9.
3.200
3.100
3.000
2.900
2.800
2.700
2.600
2.500
2.400
2.300
FIGURE 0-10.
10000
1000
100
0
Graphing is much easier because the graph paper itself takes the place of a logarithmic table, as shown in Figure 1-10.
Only the mantissa is designated by the graph paper. Scaling of the ordinate for the
characteristic is necessary. The general equation y = Be ax can be expressed as a
straight line by basic laws of indices.
ax
ln y = ln B + ln ( e ) ln y = ln B + ax
ln y = ax + ln B
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One axis is printed with logarithmic spacing, and the other with arithmetic spacing. It is used when a graph must be plotted as in the example (Figure 1-4)
y = log [ C p ] and x = t .
In this example, the vertical logarithmic axis is labelled Plasma concentration of
cyclosporine and the values plotted are the ordinary values of [ C p ] . Thus, there is
no need to use logarithmic tables, because the logarithmic spacing is responsible
for obtaining a straight line.
Two problems may occur when graphing on a logarithmic mantissa:
a) there are not enough cycles to incorporate all the data
b) obtaining the value of the slope is difficult. In this instance the slope is given by:
ln [ C p ] 2 ln [ C p ] 1
y2 y1
m = --------------- = -------------------------------------------x2 x1
t2 t1
Hence, before calculating the value of m, the two selected values of [ Cp ] 1 and [ Cp ] 2
must be converted, using a calculator, to ln [ Cp ] 1 and ln [ C p ] 2 in order to satisfy the
equation. The same problem may arise in obtaining the intercept value, b.
The two problems may be avoided by plotting the same data on ordinary paper, in
which case the vertical axis is labelled log plasma concentration. However, in
this instance the ordinary values of [ C p ] must be converted to ln [ Cp ] prior to plotting. It is the ln [ Cp ] values which are then plotted.
The calculation of the slope is direct in this case, as the values of
read from the graph.
y1
and
y2
may be
Hence, one must consider the relative merits of semilogarithmic and ordinary
paper before deciding which to use when a log plot is called for.
In the case of semilog graphs the slope may be found in a slightly different manner,
i.e., taking any convenient point on the line ( y 1 ) we usually take the as the second
point, ( y 2 ) one half of ( y 1 ) . Thus,
y1
1 -
ln -------------------
ln --------
ln y 1 ln ( ( 1 2 )y 1 )
( 1 2 )y 1
1 2
ln 2 - = 0.693
= ------------------------------= --------------------- = ------------------------m = ----------------------------------------------t 1 t2
t1 t2
t1 2
t 1 t2
t 1 t2
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2.4.12
0.693
m = ------------- = k
t1 2
and
t1 < t2 ,
then
t1 t2 = t1 2
0.693
k = ------------- .
t1 2
Functions of the type y = Bx give straight lines when plotted with logarithms
along both axis.
i.e., equation in logarithmic form is:
log y = log B + a log x or
log y = a log x + log b which is in the form
y = mx + b
This is directly applicable to parabolic and hyperbolic equations previously discussed (see Figure 1-5).
2.4.13
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FIGURE 0-11.
40
30
20
10
0
0
FIGURE 0-12.
10
15
20
25
30
40
30
20
10
1
0
2
10
20
30
Obviously, the distance (Time) on the graph 12 between 0 and 2 hours should not
be the same as the distance between 10 and 20 hours. It is, and therefore Figure 012 is wrong.
Similarly, the use of similar paper may result in some confusion. With logarithms
the mantissa for any string of numbers, differing only by decimal point placement,
is the same. What differentiates one number from another, in this case, is the characteristic. Thus,
TABLE 2-13 Logarithmic
graphing
Number
Mantissa
Characteristic
Log
234
.3692
2.3692
23.4
.3692
1.3692
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graphing
Number
Mantissa
Characteristic
Log
2.34
.3692
0.3692
0.234
.3692
-1
1.3692
Logarithmic mantissa
Logarithmic Plot
103
234
102
Y axis (units)
23.4
101
2.34
100
0.234
10-1
1.0
1.5
2.0
2.5
3.0
3.5
4.0
X axis (units)
Thus, we see, in Figure 0-13, the cycle on the semilog paper to relate to orders of
magnitude (e.g., 1, 10, 100, 1000, etc.) and consequently the characteristic of the
exponent.
The third common problem is labelling the log axis as log y. This is improper. It
is obvious from the spacing on the paper that this function is logarithmic, and thus
the axis is simply labelled y.
There are almost as many different errors as there are students and it is impossible
to list them all. These few examples should alert you to possible problems.
2.4.14
GRAPHICAL ANALYSIS
We will look at several different types of plots of data:
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FIGURE 0-14.
Find the slope by taking any two values on the Y axis such that the smaller value is
one half of the larger. The time that it takes to go from the larger to the smaller is
the half-life. Dividing 0.693 by the half-life yields the rate constant.
Extrapolating the line back to t = 0 yields the intercept.
FIGURE 0-15.
10
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FIGURE 0-16.
Curved line which goes up and then straight down on semi-log paper.
10
15
20
25
Find the terminal slope by taking any two values on the Y axis such that the
smaller value is one half of the larger. The time that it takes to go from the larger to
the smaller is the half-life. Dividing 0.693 by the half-life yields the rate constant.
Plot type one is reasonably easily evaluated. There are 2 important things that can
be obtained: Slope and Intercept. However, the slope and intercept have different
meanings dependent on the data set type plotted. The slope is the summation of all
the ways that the drug is eliminated, -K.
type 1
Data Type
Y axis
X axis
Slope
Intercept
IV Bolus Parent
Time
-K
dose
C p0 = ----------Vd
IV Bolus Parent
dXu
---------- urine rate of excretion
dt
parent compound
Time
(mid)
-K
Kr X 0
IV Bolus Parent
Xu Xu Cumulative urine
Time
-K
kr
-------------K X0
data
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Plot type two is not usually evaluated in its present form as only the plateau value
can be obtained easily. But again it has different meanings dependent on the data
plotted.
TABLE 2-15 Plot
Type 2
Y axis
X axis
Plateau Value
IV Bolus Parent
Data Type
Xu Cumulative urine
data parent compound
Time
kr
Xu = -------------K X0
IV Infusion
Parent
Drug concentration
parent compound
Time
Q - = ---Q
( C p )ss = ----------KV
cl
Usually urine data of this type (parent compound - IV bolus) is replotted and evaluated as plot 1 (above). Infusion data can be replotted using the same techniques,
but usually is not.
Plot type 3 must be stripped of the second rate constant from the early time points,
thus:
There are 3 things that can be obtained from the plot: the terminal slope (the
smaller rate constant), the slope of the stripped line (the larger rate constant) and
the intercept. The rate constants obtained from a caternary chain (drug moving
from one box to another in sequence in compartmental modeling) are the summation of all the ways that the drug is eliminated from the previous compartment and
all the ways the drug is eliminated from the compartment under consideration. See
LaPlace Transforms for further discussion.
Again, dependent on the data set type being plotted they will have different values.
Data
Type
Type 3
Y axis
X axis
S1
S2
Intercept
IV Bolus
Parent
Metabolite conc.
Time
-Ksmall
-Klarge
km X 0
------------------------------------------------------( K l arg e K small ) V dm
IV Bolus
Parent
dXmu
--------------- excretion
dt
rate of metabolite
into urine
Time
(mid)
-Ksmall
-Klarge
k mu k m X 0
-----------------------------------K l arg e K small
Oral
Drug conc.
Time
-Ksmall
-Klarge
k a fX 0
--------------------------------------------------( K l arg e K small ) V d
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define all new words used in this section. e g.: Succinctly define, stating rigorously the meaning
of any symbols used and the dimensions of measurement.
compare and contrast new concepts used in this section. e. g.: rate and rate constant, zero and
first order kinetics, bolus and infusion methods, excretion and elimination, the assumptions
made in pharmacokinetic models with physiological reality. Why can these assumptions be
made?
pictorially represent any two variables (graph) one vs. the other. e.g. for each of the following
pairs of variables (ordinate against abscissa), draw a graph illustrating the qualitative profile of
their relationship. Where appropriate, indicate the nature of important slopes, intercepts, and
values. Unless you specifically indicate on your plot that semi-log paper is being considered
(write S-L), it will be assumed that rectilinear paper is being considered. Graphs are for a
drug given by IV Bolus where applicable.
2.5.1
MAKING A MODEL
ka
The picture that we build is made up of building blocks, consisting of the arrow
and what the arrow touches. The arrow demonstrates how quickly the mass of
drug, X , declines. The arrow times the box that the arrow touches = the rate. Rates
can go in, i.e. arrows pointing to a box mean drug is going in (+ rate). Rates can go
out, i.e. arrows pointing away means drug is going out (- rate). Rate = rate constant
(arrow) times mass of drug (box). So the arrow and box really is a pictorial representation of a rate where the rate is the rate constant on the top of the arrow times
what the tail of the arrow touches.
Again, the rate constant, k , tells the magnitude of the rate,
kX.
X1
k12
X2
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X3
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The building blocks are k 12 X1 and k 23 X2 . Every arrow that touches the compartment of interest becomes part of the differential equation. If the arrow goes to the
box, its positive; if it goes away from the box, its negative.
To find dX 1 dt (the rate of change of X 1 with time), we simply add up all of the
rates which affect X1 (all of the arrows that touch X1 )
dX 1
--------- = k 12 X 1
dt
and thus:
dX 2
--------- = k 12 X 1 k 23 X2
dt
dX 3
--------- = k 23 X 2
dt
(Note: the first subscript of the rate constant and the subscript of the box from
which it originates are the same.)
You should be able to develop the series of interdependent differential equations
which would result from any model. The integration of those equations by use of
the Laplace Table is done by transforming each piece of the equation into the
Laplace domain (looking it up on the table and substituting). The algebra performed solves for the time dependent variable: put everything except the variable
(including the operator, s) on the right side and put the variable on the left. Find the
resulting relationship on the left side of the table. The corresponding equation on
the right side of the table in the integrated form.
You should be able to integrate any differential equation developed from any
model (within reason) that we can conceptualize.
(Note: Each subsequent variable is dependent on the ones that precedes it. In fact,
the solutions to the preceding variables are substituted into the differential to
remove all but one of the time dependent functions - the one that we are currently
attempting to solve.)
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2.5.2
It is important to note that we know some of these assumptions are not true. It is of
little consequence, as the data acts as if these were true for many drugs. The visual
image which is useful is one of a single box and a single arrow going out of the
box depicting one compartment with linear kinetics. The dose is placed in the box
and is eliminated by first order processes. In many cases, more complicated models (more boxes) are necessary to mathematically mimic the observed plasma versus time profile when one or more of these assumptions are not accurate. For
example, the two compartment (or multi-compartment) model results when the
body is assumed to not be homogeneous and distribution is not instantaneous.
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integrated, the final equation will describe the mass of drug actually in the body at
any time.
The procedure used is to replace the Independent variable (time) by a function
containing the LaPlace Operator, whose symbol is s. In doing so we have
replaced the time domain by a complex domain. This is analogous to replacing a
number by its logarithm. Once in the complex domain, the transformed function
may be manipulated by regular algebraic methods. Then the final expression in the
complex domain is replaced by its equivalent in the time domain, yielding the integrated equation. This ultimate process is analogous to taking an antilogarithm.
2.6.1
2.6.2
As
, then f ( t ) is At .
SYMBOLISM
For simplicity in writing transformed rate expressions (and to distinguish them
from untransformed (time domain) expressions), the following symbolism will be
employed:
a bar will be placed over the dependent variable which is being transformed.
Example:
If X is the mass of unchanged drug in the body at any time, then X is the LaPlace
Transform of this mass.
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2.6.3
Body
Urine
Dose
kf
Parent Compound
Xf
ku
X
Xu
km
kmf
Metabolite
Xmf
kmu
Xm
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Using the pharmacokinetic symbolism from chapter one, the compartments are
named and placed: metabolites below (or above the plane of the parent compound): compounds going into the urine, to the right; and compounds going into
the feces, to the left of the compounds in the body. The rate constants connecting
the compartments also follow the symbolism from chapter one. In the above flow
chart, K1, the summation of all the ways that X is removed from the body, is ku +
kf + km while K2, the summation of all the ways that Xm is removed from the
body, is kmu +kmf.
Only those compartments are used which correspond to the drugs pharmacokinetic description, thus when a drug is given by IV bolus and is 100% metabolized
with the metabolite being 100% excreted into the urine the model would look like
this:
Dose
X
km
kmu
Xm
Xmu
Thus in this flow chart, K1, the summation of all the ways that X is removed from
the body, is km while K2, the summation of all the ways that Xm is removed from
the body, is kmu.
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Drugs sometimes are metabolized to two (or more) different metabolites. In the
first case, the drug is metabolized by two separate pathways resulting in this flow
chart:
Xmf1
kmf1
Xm1
Dose
Xf
kf
kmu1
Xmu1
km1
ku
Xu
km2
Xmf2
kmf2
kmu2
Xm2
Xmu2
In this flow chart, K1, the summation of all the ways that X is removed from the
body, is ku + kf + km1 + km2 while K2, the summation of all the ways that Xm1 is
removed from the body, is kmu1 +kmf1 and K3, the summation of all the ways
that Xm2 is removed from the body, is kmu2 + kmf2.
While in a second case, the drug is metabolized and the metabolite is further
metabolized resulting in this flow chart:
Dose
Xf
kf
ku
Xu
km1
Xmf1
kmf1
Xm1
kmu1
Xmu1
km2
Xmf2
kmf2
Xm2
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Xmu2
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In this flow chart, K1, the summation of all the ways that X is removed from the
body, is ku + kf + km1 while K2, the summation of all the ways that Xm1 is
removed from the body, is kmu1 +kmf1+ km2 and K3, the summation of all the
ways that Xm2 is removed from the body is kmf2 + kmu2.
Both of these flow charts result in very different end equations, so it is imperative
that the flow charts accurately reflect the fate of the drug.
2.6.4
Take the LaPlace Transform of each side of the differential rate equation, using the table where
necessary.
Algebraically manipulate the transformed equation until an equation having only one transformed dependent variable on the left-hand side is obtained.
Convert the transformed expression back to the time domain, using the table where necessary to
yield the Integrated equation.
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2.6.5
(Scheme I)
ku
Xu
(EQ 1-18)
(EQ 1-19)
Note that because the independent variable (time) did not appear on the right-hand
side of equation 1-18, neither did the LaPlace Operator, s, appear there in equation
1-19. All that was necessary was to transform the dependent variable ( X ) into X .
Hence, the table was only required for transforming the left-hand side of equation
1-19.
Manipulating the transformed equation:
1. Get only one variable which changes with time
2. Get
(X)
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sX + k u X = X0
X ( s + k u ) = X0
X0
X = ------------s + ku
LetX 0 = A
Letk u = a
(EQ 1-20)
A
X = ---------------(s + a)
(EQ 1-21)
Note that X is the only transformed dependent variable and is on the left-hand side
of equation 1-20.
Converting back to the time domain:
X = X0e
ku t
(EQ 1-22)
A
Note that the right-hand side of equation 1-22 was analogous to ---------------- in the
(s + a)
table, because X0 is a constant (the initial dose administered). The left-hand side
of equation 1-22 could be converted back without the table.
The final expression is the familiar first-order integrated expression.
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2.6.6
(EQ 1-23)
(EQ 1-24)
But, at zero time, the cumulative mass of unchanged drug in the urine was zero:
that is ( Xu ) 0 = 0 .
sX u = k u X
(EQ 1-25)
(EQ 1-26)
Note that there are two transformed dependent variables. One of them ( X ) can be
replaced by reference to equation 1-20.
ku X0
Xu = -------------------s(s + ku)
Let ( k u X0 ) = A
Let ( k u ) = a
(EQ 1-27)
A
X = -----------------s(s + a)
(EQ 1-28)
kuX0 ( 1 e u )
X u = ---------------------------------------ku
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2.6.7
kut
(EQ 1-29)
Infusion
ku
Xu
Where Q is the zero-order infusion rate constant (the drug is entering the body at a
constant rate and the rate of change of the mass of drug in the body is governed by
the drug entering the body by infusion and the drug leaving the body by excretion).
The drug entering the body does so at a constant (zero-order) rate.
dX
------- = Q k u X
dt
(EQ 1-30)
(EQ 1-31)
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(EQ 1-32)
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Let ( Q = A )
A
X = ------------------s( s + a)
Let ( k u = a )
(EQ 1-33)
Q(1 e )
X = ----------------------------ku
2.6.8
(EQ 1-34)
CONCLUSIONS
The final integrations (Eqs. 24, 24, and 28) are not the ultimate goal of pharmacokinetics. From them come the concepts of:
1.
1.
2.
These, and other concepts arising from still other equations, are clinically useful.
Once the method of LaPlace Transforms is mastered, it becomes easy to derive
equations given only the required pharmacokinetic scheme. Under such circumstances, it no longer becomes necessary to remember a multitude of equations,
many of which, though very similar, differ markedly in perhaps one minute detail.
As with any new technique, practice is required for its mastery. In this case, mastery will banish the calculus blues.
It is also possible to see certain patterns which begin to emerge from the derivation
of the equations. For example, for a drug given by IV bolus the equation is
monoexponential, with the exponent being K1, summation of all the ways that the
drug is removed form the body. A graph of the data (Cp v T on semi-log paper)
results in a straight line the slope of which is K1, always. If the drug is entirely
metabolized K1 = km. If the drug is entirely excreted unchanged into the urine,
K1 = ku. If the drug is metabolized and excreted unchanged into the urine, K1 =
km +ku. thus K1 can have different meanings for different drugs, depending on
how the body removes the drug. Following the drug given by IV bolus a second
example of a pattern would be that of the data of the metabolite of the drug. From
the LaPlace, the equation for the plasma concentration of the metabolite of the
drug has in it K1 and K2, the summation of all the ways that the metabolite is
removed from the body, always. K2 would have different meanings depending on
how the metabolite is removed from the body.
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After several years teaching, I was fortunate to have a resident rotate through our
pharmacokinetic site. She had come with a strong Pharmacokinetcs background
and during our initial meeting, she had told me that she had a copy of John Wagners new textbook on pharmacokinetcs. She was excited that, finally, there was a
compilation of all the equations used in pharmacokinetics in one place.
There are over 500 equations in the new book and I know every one, she said.
Im not sure which one goes with which situation, though. OOPS!
Throughout this text and on each exam, each equation is derived from first principles using scientific method, modeling and LaPlace Transforms in the hopes that
memorization will be minimized and thought (and consequently proper interpretation) would be maximized.
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2.6.9
A, B
are constants
a, b, c
is a power constant
of LaPlace Transforms
Time Function, F ( t )
LaPlace Transform, f ( s )
A
--s
At
A
---2
s
A
( m! -)
-------------m+1
s
at
A
----------s+a
m at
A
-------------------------m+1
(s + a)
At
Ae
At e
at
A
------------------s (s + a )
A(1 e )
-------------------------a
at
A( 1 e )
At
----- -------------------------2
a
a
A
--------------------2
s (s + a)
at
As B-----------------s (s + a )
Ae
at
B( 1 e )
-------------------------a
at
e - Bt
A + B
--- 1--------------------
a a
a
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--------------------2
s (s + a)
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of LaPlace Transforms
Time Function, F ( t )
bt
LaPlace Transform, f ( s )
at
A
-------------------------------(s + a)(s + b)
A( e e )
--------------------------------(a b)
A
e - 1---------------- e -
1-------------------------------
(a b)
b
a
A
-----------------------------------s( s + a )( s + b )
1 e bt 1 e at
At
A
------ ---------------- ------------------ ------------------
ab ( a b ) b2 a2
A
-------------------------------------2
s ( s + a) ( s + b)
1 [ ( B + Aa )e at ( B + Ab )e bt ]
---------------( a b)
As B -------------------------------(s + a)(s + b)
( 1 e bt ) ( 1 e at )
bt
at
1
---------------- A ( e e ) B ---------------------- ----------------------
(a b)
b
a
As B
-----------------------------------s( s + a )( s + b )
( 1 e bt )
( 1 e at )
1
B
B
Bt
---------------A
+
-----------------------
A
+
--
---------------------- -----(a b)
b
b
a
a
ab
As B
-------------------------------------2
s ( s + a) ( s + b)
bt
ct
at
bt
at
e
e
e
A -------------------------------- + --------------------------------+ --------------------------------(a c)(b c) (a b )(c b) (b a )(c a)
ct
bt
at
(1 e )
(1 e )
(1 e )
A ------------------------------------ + ------------------------------------- + ------------------------------------c( a c )( b c ) b( a b)( c b ) a( b a )( c a)
A
------------------------------------------------(s + a)(s + b)(s + c)
A
---------------------------------------------------s( s + a )( s + b )( s + c )
(1 e )
(1 e )
(1 e )
At- A -----------------------------------------+ --------------------------------------- + --------------------------------------2
2
2
bc
c ( a c) ( b c ) b ( a b) ( c b) a ( b a )( c a)
A
------------------------------------------------------2
s ( s + a) ( s + b ) ( s + c )
dX
------dt
sX X 0
ct
bt
at
(m + 1 )
A
----m
s
At
------------------(m + 1)
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2.6.10
The amount of drug in the body when the drug is given by IV Bolus (assume no metabolism).
2.
The amount of drug in the urine when the drug is given by IV Bolus (assume no metabolism).
3.
The amount of metabolite in the body when the drug is given by IV Bolus (assume no parent
drug excretion)
4.
The amount of metabolite of the drug in the urine when the drug is given by IV Bolus (assume
no parent drug excretion)
5.
The amount of metabolite of the drug in the urine when the drug is given by IV Bolus (assume
both parent drug and metabolite excretion)
6.
The amount of drug in the body when the drug is given by IV infusion (assume no metabolism).
7.
The amount of drug in the urine when the drug is given by IV infusion (assume no metabolism).
8.
The amount of metabolite in the body when the drug is given by IV infusion (assume no parent
drug excretion).
9.
The amount of metabolite in the urine when the drug is given by IV infusion (assume no parent
drug excretion).
10.
The Rate of excretion of the metabolite into the urine for a drug given by IV bolus when
km+ku=kmu.
11.
The amount of the principle metabolite (Xm1) when the drug is eliminated by several pathways
(Xu, Xm1,Xm2,Xm3,etc)
12.
The amount of metabolite of a drug in the body when the drug is given by IV Bolus and concomitant IV infusion.
14.
Disopyramide (D) is a cardiac antiarrythmic drug indicated for the suppression and prevention
of ectopic premature ventricular arrythmias and ventricular tachycardia. It appears that disopyramide is metabolized by a single pathway to mono-dealkylated disopyramide (MND). In a
recent study, the pharmacokinetics of disopyramide were attempted to be elucidated by means
of a radioactive tracer. Since both D and MND would be labeled by the tracer, any equations
showing the time course of the label would show both the D and MND. By means of the
laPlace transform, find the equation for the rate of appearance of tracer into the urine if the drug
were given by IV Bolus.
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2.6.11
1. The amount of drug in the body when the drug is given by IV bolus (assume no metabolism).
Dose
X
ku
Xu
dX
------- = k u X
dt
sX X0 = kuX
sX + kuX = X o
X ( s + k u )= Xo
Xo
X = ------------s + ku
kut
A
Let ( X0 ) = A , k u = a ,X = ---------------X = Xo e
(s + a)
2. the amount of a drug in the urine when the drug is given by IV bolus (assume the drug is NOT metabolized
Dose
X
ku
Xu
Again K1 = ku
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dX
--------u- = k u X
dt
sX Xo = k m X
sX + k m X = Xo
sX u Xuo = k u X
X ( s + k m ) = Xo
sX u = k u X
Xo
X = -------------s + km
X o ku
sX u = -----------------(s + ku)
A
Let ( X 0 ) = A , k m = a , X = ---------------(s + a)
Xo ku
X u = -------------------s(s + ku)
X = Xo e
A
Let ( X0 k u ) = A , k u = a , X u = -----------------s( s + a )
kmt
dX m
---------- = k m X k mu X m
dt
kut
ku X o ( 1 e
)
X u = -----------------------------------ku
Xu= Xo ( 1 e
kut
sX m Xm0 = k m X kmu X m
km X 0
sX m = ------------- k mu Xm
s + km
3.
the amount of metabolite of a drug in the body
when the drug is given by IV bolus (assume no parent
drug excretion).
km Xo
X m = ----------------------------------------( s + k mu ) ( s + k m )
Let ( k m X 0 ) = A , k m = a = K1 , k mu = b = K2
A
X m = --------------------------------(s + a)(s + b )
Dose
( km X o )
k t
k t
X m = ------------------------ ( e mu e m ) or
( k m k mu )
( km Xo )
K 2t
K 1t
X m = ------------------------ (e
e
) in general terms.
( K1 K2 )
km
Xm
kmu
Xmu
Let ( k m X 0 ) = A , k m = b , k mu = a
Here K1 = km and K2 = kmu
and then
dx
------ = k m X
dt
( km X o )
k t
k t
X m = ------------------------ ( e m e mu ) or
( k mu k m )
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( km Xo )
K 1t
K2t
(e
e
)
X m = ------------------------( K2 K1 )
dX mu
------------- = k mu Xm
dt
sX mu Xom = k mu X m
4.
the amount of metabolite of a drug in the urine
when the drug is given by IV bolus (assume the parent
compound is not excreted).
X om = 0
sX mu = k mu X m
Dose
( k mu ) ( k m X o )
sX mu = ----------------------------------------( s + k mu ) ( s + k m )
( k mu ) ( k m ) ( X o )
X mu = -------------------------------------------s ( s + kmu ) ( s + k m )
k mu k m Xo 1 e kmt 1 e kmut
X mu = -------------------- --------------------- -----------------------
k mu k m k m
k mu
km
Xm
kmu
Xmu
5.
the amount of metabolite of a drug excreted in
the urine when both the parent and metabolite are
excreted.
dXm
----------- = k m X k mu X m
dt
sX m Xom = k m X kmu X m
Dose
sX m + k mu Xm = k m X
X
s + km
o
substitute previously solved X = --------------
Xm
km X o
X m = ----------------------------------------( s + k mu ) ( s + k m )
kmt
kmut
Xu
kmu
Xmu
km
km Xo
X m ( s + k mu ) = -------------s + km
km Xo ( e
e
)
X m = -------------------------------------------------( k mu k m )
ku
dX
------- = k u X k m X
dt
sX Xo = k u X k m X
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sX + k u X + k m X = X o
X ( s + ku + km ) = Xo
ku
Xu
( k u + k m ) = K1
Xo
X = --------------s + K1
X = Xo e
K1t
dXm
------------ = k m X k mu Xm = k m X K2Xm
dt
sXm X om = k m X K2Xm
dX
------- = Q k u X
dt
---- K u X
sX X0 = Q
s
sX m + K2Xm = k m X
Q
sX + k u X = --s
km Xo
X m = ----------------------------------------( s + K2 ) ( s + K1 )
Q X = -------------------s ( s + ku )
dX mu
------------ = k mu Xm
dt
Q- ( 1 e k u t )
K1t
Q
X = ---)
or X = ------- ( 1 e
ku
K1
sX mu Xom = k mu X m = K2Xm
sX mu = K2X m
( k mu ) ( kmX o )
sX mu = ----------------------------------------( s + K2 ) ( s + K1 )
( k mu ) ( k m ) ( Xo )
X mu = -------------------------------------------s ( s + K2 ) ( s + K1 )
k mu k m X o 1 e K1t 1 e K2t
X mu = --------------------- --------------------- --------------------K2 K1 K1
K2
7.
the amount of drug in the urine when the drug is
given by infusion (assume the drug is NOT metabolized).
ku
Xu
Here K1 = ku
dX
------- = Q k u X
dt
6. The amount of drug in the body from a drug given by
IV infusion (assume no metabolism).
Q- k X
sX Xo = --u
s
QsX + k u X = --s
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QX (s + k u ) = --s
dX
------- = Q k m X
dt
Q
X = ------------------------s (s + ku )
Q- k X
sX Xo = --m
s
dX
--------u- = k u X
dt
sX + k m X = Q
---s
sX u Xo = k u X
QX ( s + k m ) = --s
sX u = k u X
Q
X = --------------------s ( s + km )
ku Q
sX u = ------------------------s (s + ku)
kmt
(1 e
)
X = Q -------------------------km
ku Q
X u = --------------------------2
s ( s + ku )
dX m
---------- = k m X k mu X m
dt
e kut
k u Qt
X u = ---------- Qk u 1-------------------
ku
k2
sX m Xo = k m X k mu Xm
kut
K1t
(1 e
)
(1 e
)
X u = Qt Q ------------------------- or Xu = Qt Q -------------------------ku
K1
8.
the amount of metabolite of a drug in the body
from a drug given by IV infusion (assume no parent drug
excretion) Here K1 = km and K2 = kmu
sX m = k m X k mu Xm
km Q
X m = -------------------------------------------s ( s + k mu ) ( s + k m )
A
X m = ---------------(a b)
bt
at
e 1 e -
1---------------- b - ----------------a
1 e k m t 1 e k mut
km Q
X m = ------------------------ -------------------- --------------------- or
( k mu k m ) k m k mu
K1t
K2t
kmQ
e - 1------------------- e -
1-------------------X m = ------------------------( K2 K1 ) K1 K2
X
km
Xm
kmu
Xmu
9.
the amount of metabolite of a drug in the urine
from a drug given by IV infusion (assume that the parent
compound is not excreted). Here K1 = km and K2 = kmu
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sX mu Xomu = k mu X m substitute X m
k mu k m Q
X mu = ---------------------------------------------2
s ( s + k m ) ( s + k mu )
k mu k m Qt k mu k m Q ( 1 e kmut ) ( 1 e kmt )
X mu = --------------------- --------------------- ----------------------------- --------------------------
2
2
k m k mu k m k m u
k
k
km
mu
Xm
kmu
Xmu
or
k mu k m Qt k mu k m Q ( 1 e K2t ) ( 1 e K1t )
X mu = --------------------- -------------------- -------------------------- --------------------------
2
2
K1 K2 K1 K2
K2
K1
dX
------- = Q k m X
dt
Q
sX Xo = ---- k m X
s
sX + k m X = Q
---s
X ( s + km ) = Q
---s
Q X = --------------------s ( s + km )
10.
the rate of excretion of the metabolite into the
urine for a drug given by IV bolus when
k m + k u = k mu
In this case, K1 = ku +km and K2 = kmu and thus K1 =
K2. This is not normal but could happen. The problem
arises when we get to the LaPlace that assumes the rate
constants are different (i.e. a b ) because for this special
case a = b .
dX m
---------= k m X k mu X m
dt
Dose
sX m Xo = k m X k mu Xm
X
sX m + k mu X m = k m X
km Q
X m ( s + k mu ) = --------------------s ( s + km )
dX mu
------------ = k mu Xm
dt
Xu
kmu
Xmu
km
Xm
km Q
X m = -------------------------------------------s ( s + k m ) ( s + k mu )
k m Q 1 e kmut 1 e kmt
X m = -------------------- ----------------------- ---------------------
k m k mu k mu k m
ku
dX
. ------- = k u X k m X
dt
sX Xo = k u X k m X
sX + k u X + k m X = X o
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X ( s + ku + km ) = Xo
11.
Xo
X = -----------------------------( s + k u + km )
K1 = ( k u + k m )
k mu = K2
Xm1
Xo
X = -------------------( s + K1 )
X = Xo e
Dose
kmu1
Xmu1
km1
K1t
ku
Xu
dX m
---------= ( k m X k mu X m )
dt
km2
sX m Xom = ( k m X K2X m )
Xm2
sX m + K2X m = k m X
km X o
X m ( s + K2 ) = -----------s+K
km Xo
X m = ----------------------------------------( s + K2 ) ( s + K1 )
X m = k m Xo te
Xmu2
dX
------- = k u X k m1 X k m2 X
dt
(remember- K2 = K1)
km Xo
X m = ----------------------------------------( s + K1 ) ( s + K1 )
km Xo
X m = ---------------------2
( s + K1 )
kmu2
sX Xo = k u X k m1 X k m2 X
sX + k u X + k m1 X + k m2 X = X o
X ( s + k u + k m1 + k m2 ) = Xo Let K1 = ku + km1 + km2
(kmX0 = A)
K1t
dX mu
------------ = k mu Xm
dt
dX mu
K1t
------------ = k mu k m Xo te
dt
Xo
X = -------------------( s + K1 )
K1 = ( k u + k m1 + k m2 ) and K2 = k mu1
dX m1
------------- = k m1 X K2X m1
dt
sX m1 Xm1o = k m1 X K2X m1
X m1o = 0
k m1 Xo
sX m1 + K2X m1 = -------------------( s + K1 )
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k m1 Xo
X m1 ( s + K2 ) = -------------------( s + K1 )
Xo= 0
ka Q
sX + K1X = -------------------s ( s + ka )
k m1 X o
X m1 = ----------------------------------------( s + K1 ) ( s + K2 )
ka Q
X ( s + K1 ) = -------------------s ( s + ka )
k m1 Xo K1t K2t
(e
e
)
X m1 = -------------------K2 K1
ka Q
X = -----------------------------------------s ( s + k a ) ( s + K1 )
12.
the concentration of drug X Vd in the body
when the drug is given orally by a delivery system which
is zero order. What is the concentration in the body at
equilibrium ( t )
Here K1 = ku
ka
Xa
ku
Xu
k a Q ( 1 e K1t ) ( 1 e kat )
X = ---------------------- --------------------------- -------------------------
ka
K1
( k a K1 )
ka Q
( 1 e K1t ) ( 1 e kat )
C = ----------------------------- --------------------------- -------------------------
( k a K1 )Vd
K1
ka
k Q
1
1
a
If t= , then e kt = 0 , thus C = ----------------------------- ------- -----
( k a K1 )Vd K1
ka
Q
simplified yields: C = --------------
dX
--------a- = Q k a X a
dt
Q
sX a Xao = ---- k a Xa
s
K1Vd
13
the metabolite of a drug in the body Xm given
by IV infusion and concomitant IV bolus dose.
Infusion:
Here K1 = km and K2 = kmu
X a0 = 0
Dose
sX a + k a Xa = ( Q s )
X a ( s + ka ) = ( Q s )
Q X a = -------------------s(s + ka)
X
km
kat
Q( 1 e )
X a = ----------------------------ka
Xm
kmu
Xmu
dX
------- = k a X a K1X
dt
sX Xo = k a Xa k1X
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dX
------- = Q K1X
dt
dX m
---------- = k m X K2X m
dt
sX Xo = Q
---- K1X
s
sX m Xo = k m X K2X m
sX + K1X = Q
---s
sX m + K2X m = k m X
X ( s + K1 ) = Q
---s
Q
X = ----------------------s ( s + K1 )
dX m
---------= k m X K2X m
dt
km X o
X m ( s + K2 ) = --------------s + K1
km Xo
X m = ----------------------------------------( s + K1 ) ( s + K2 )
km Xo
K2t
K 1t
X m = ------------------------(e
e
)
( K1 K2 )
Thus,
sX m Xo = k m X K2Xm
sX m + K2X m = k m X
km Q
X m ( s + K2 ) = ----------------------s ( s + K1 )
km Q
X m = -------------------------------------------s ( s + K1 ) ( s + K2 )
k m Q ( 1 e K1t ) ( 1 e K2t )
X m = ------------------------- -------------------------- --------------------------
( K2 K1 )
K1
K2
km X o
K2t
K 1t
(e
e
) + below
X m = ------------------------( K1 K2 )
k m Q ( 1 e K2t ) ( 1 e K1t )
-------------------- -------------------------- --------------------------
K2
K1
K1 K2
14.
By means of the LaPlace transform, find the
equation for the rate of appearance of the tracer in the
urine if the drug were given by IV bolus.
Here K1 = ku + km and K2 = kmu
IV Bolus:
dX
------- = K1X
dt
Dose
sX Xo = K1X
ku
Xu
kmu
Xmu
sX + K1X = X o
km
X ( s + K1 ) = Xo
Xm
Xo
X = --------------s + K1
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dX
------- = k u X k m X
dt
sX Xo = k u X k m X
sX + k u X + k m X = X o
X ( s + ku + km ) = Xo
( k u + k m ) = K1
Xo
X = -------------------( s + K1 )
X = Xo e
K1t
dX
K1t
--------u- = k m X = k u ( Xo e
)
dt
dX m
---------= k m X K2X m
dt
sX m Xo = k m X k2Xm
k m Xo
sX m + K2X m = -------------------( s + K1 )
km X o
X m ( s + K2 ) = --------------s + K1
km Xo
X m = ----------------------------------------( s + K2 ) ( s + K1 )
km Xo
K1t
K2t
X m = ------------------------{e
e
}
( K2 K1 )
k mu k m Xo K1t K2t
dX mu
------------ = k mu Xm = ------------------------{e
e
}
dt
( K2 K1 )
k mu k m X o
dX u dX mu
K1t
{ e K1t e K2t }
--------- + ------------- = k u ( X o e
) + ------------------------
( K2 K1 )
dt
dt
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CHAPTER 3
Pharmacological Response
OBJECTIVES
After completing this chapter, the student will be able to:
1.
Given patient data of the following types, the student will be able to properly construct (III) a graph and compute (III) the slope using linear regression: response
(R) vs. concentration (C), response (R) vs. time (T), concentration (C) vs. time (T)
2.
Given any two of the above data sets, the student will be able to compute (III) the
slope of the third by linear regression.
3.
Give response vs. time and response versus concentration data, the student will be
able to compute (III) the terminal (elimination) rate constant and half life of the
drug.
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Pharmacological Response
3.1.1
One theory (A.J. Clarke) on the mechanism of action of drugs is the occupation
theory. It suggests that the intensity of a pharmacological response (E) is proportional to the concentration of a reversible drug-receptor complex
(EQ 1-35)
PKAnalyst Plot
1.0
0.8
0.6
If
0.4
is plotted against
[D]
E max .
0.2
0.0
0.0
0.8
1.6
2.4
3.2
4.0
X = V Cp ,
a plot of
against
will be
c. For a series of doses the value of X at the same given time after dosing is proportional to the dose (D). Thus, a plot of E against D will also be hyperbolic at a specific time.
d. Any hyperbolic curve, if plotted on reverse semilogarithmic paper (i.e., abscissa
is logarithmic), has a sigmoid shape. If we plot E against Cp (of X , or D ) in this
manner, the plot is virtually linear in the range E Emax = 0.2 0.8 ; and if this is the
clinical range of responses, linear equations may be written. For example,
1.0
Response
0.8
0.6
0.4
0.2
0.0
10 -810-710 -610-510 -410 -310-210 -1
E = m ln x + b
Conc.
where
is the slope
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Pharmacological Response
3.1.2
This example equation shows that, in the clinical range, the intensity of a pharmacological response is proportional to the logarithm of the administered dose, providing response is measured at a consistent time after dosing. The proportionality
constant (slope, m ) is a function of the affinity of the drug for the receptor. In fact,
equation yields a log-dose response plot. Note that doubling the dose does not
double the response.
You should know what the various graphical relationships look like. Response vs.
natural log of concentration is sigmoidal. (S shaped). We are interested in the middle almost straight part. The slope is dR d ln c .
Response vs. time is a straight line. The slope is
dR dt .
Natural log of concentration vs. time (drug given by IV bolus) is a straight line.
The slope is d ln c dt .
You should be able to obtain the slope of each of these relationships from data sets.
You should be able to obtain the third slopes relationship given the other two (or
data sets with which to get the other two).
dR
dR d ln c
------- = ----------- ----------dt
d ln c dt
dR
dR dt
----------- = -------------------d ln c
d ln c dt
(EQ 1-36)
(EQ 1-37)
d ln c
dR dt
(EQ 1-38)
----------- = ---------------------dt
dR d ln c
You should be able to apply the equation y = mx + b to each of the above relationships. Given the slope (or having obtained the slope) and two of the three variables
(y, x, b), you should be able to find the third.
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Pharmacological Response
Kt
= De
Kt
(EQ 1-39)
or
Ln ( X ) = Ln ( D ) Kt
(EQ 1-40)
Substituting twice from eq. once at time t and once at zero time
E
b = E
0b
------------------------- Kt E = E0 Rt
m
m
(EQ 1-41)
3.2.2
Response follows
plasma profile.
3.2.3
Because E is proportional to ln x at any time, a plot of E against t will be analogous to a plot of ln x against t . Hence E will rise at first and then decline with time.
When t is large, the terminal slope will be R .
Duration of action is
related to how long
plasma concentration is
above Minimum Effective Concentration.
Kt dur
(EQ 1-42)
Rearranging,
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Pharmacological Response
t dur
D
ln -------X
eff
= ------------------K
(EQ 1-43)
(EQ 1-44)
Thus a plot of duration of action vs ln dose would result in a straight line with a
slope of 1/K and an x intercept of
3.2.4
ln ( X eff )
.
------------------K
3.2.5
a. Obtain a log dose-response plot (Eq. 1-37). The response must always be measured at the same time after administering the dose.
(m)
of this plot.
c. Obtain a response against time plot for a single dose (Eq. 1-36).
d. Find the terminal slope
e. Calculate
R
K = ---- .
m
f. Calculate
0.693
t 1 2 = -------------
K
( R )
of this plot.
DELAYED RESPONSE
Two compartment
model - biophase is in
second compartment.
If a drug does not distribute instantaneously to all the body tissues (including the
active site), the pharmacological response will not always parallel the drug concentrations in the plasma. In such a situation the response may parallel the mass of
drug presumed to be in a second compartment ( X 2 ) , and hence seem delayed.
Eventually, however, once equilibrium is attained, the response will parallel
plasma concentrations. In such a case, E is proportional to ln X 2 .
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Pharmacological Response
Thus a plot of E against X1 (or E against Cp ) will show a hysteresis loop with time,
most noticeably during an intravenous infusion.
3.2.6
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Pharmacological Response
There exists a fundamental relationship between drug pharmacokinetics and pharmacologic response. The relationship between response and ln-concentration is
sigmoidal. A threshold concentration of drug must be attained before any response
is elicited at all. Therapy is achieved when the desired effect is attained because
the required concentration has been reached. That concentration would set the
lower limit of utility of the drug, and is called the Minimum Effective Concentration (MEC). Most drugs are not clean, that is exhibit only the desired therapeutic response. They may also exhibit undesired side effects, sometimes called toxic
effects at a higher, (hopefully a lot higher), concentration. At some concentration,
these toxic side effects become become intolerable/and or dangerous to the
patient.. That concentration, or one below it, would set the upper limit of utility
for the drug and is called the Maximum Therapeutic Concentration or Minimum
Toxic Concentration (MTC). Patient studies have generated upper (MTC) and
lower (MEC) plasma concentration ranges that are deemed safe and effective in
treating specific disease states. These concentrations are known as the therapeutic
range for the drug (Table 2-18).
When digoxin is administered at a fixed dosage to numerous subjects, the blood
concentrations achieved vary greatly. Clinically, digoxin concentrations below 0.8
ng ml will elicit a subtherapeutic effect. Alternatively, when the digoxin concentration exceeds 2.0 ng ml side effects occur (nausea and vomiting, abdominal pain,
visual disturbances). Drugs like digoxin possess a narrow therapeutic index
because the concentrations that may produce toxic effects are close to those
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3-7
Pharmacological Response
required for therapeutic effects. The importance of considering both pharmacokinetics and pharmacodynamics is clear.
TABLE 2-18 Average
DRUG
RANGE
digoxin
0.8-2.0 ng ml
gentamicin
2-10 g ml l
lidocaine
1-4 g ml
lithium
0.4-1.4 mEq L
phenytoin
10-20 g ml
phenobarbitol
10-30 g ml
procainamide
4-8 g ml
quinidine
3-6 g ml
theophylline
10-20 g ml
drug-drug interactions
patient disease state
physiological states such as age, weight, sex
drug absorption variation
differences in the ability of a patient to metabolize and eliminate the drug
If we were to give an identical dose of drug to a large group of patients and then
measure the highest plasma drug concentration we would see that due to individual
variability, the resulting plasma drug concentrations differ. This variability can be
attributed to factors influencing drug absorption, distribution, metabolism, and
excretion. Therefore, drug dosage regimens must take into account any disease
altering state or physiological difference in the individual.
Therapeutic drug monitoring optimizes a patients drug therapy by determining
plasma drug concentrations to ensure the rapid and safe drug level in the therapeutic range.
Two components make
up the process of
therapeutic drug
monitoring:
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Pharmacological Response
The major potential advantages of therapeutic drug monitoring are the maximization of therapeutic drug benefits and the minimization of toxic drug effects. The
formulation of drug therapy regimens by therapeutic drug monitoring involves a
process for reaching dosage decisions.
3.3.1
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3-9
Pharmacological Response
hospital makes money. If the days cost more than the hospital loses money. This
study showed that if all patients in the hospital who were on gentamicin were monitored, the hospital would save $4,000,000. Thats right FOUR MILLION per year.
I would say that would pay my salary, with a little left over, and that is only one
drug!
The process of
therapeutic monitoring
takes effort.
You must follow through to ensure proper changes have been made.
You must continue the process throughout therapy. Therapeutic drug monitoring, in many cases,
will be part of your practice. It can be very rewarding.
1. Nagashima, R., OReilly, RA., and Levy, G, Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin. Clin.
Pharm. Therap, 10 22-35 (1969).
2. Wagner, J.G, Relations between drug concentration and response. J. Mond. Pharm., 4, 279-310 (1971).
3. Gibaldi M. and Levy, G. Dose-dependent decline of pharmacologic effects of drugs with linear pharmacokinetics characteristics. J.Pharm.Sci, 61, 567-569 (1972).
4. Brunner, L., Imhof, P., and Jack, D. Relation between plasma concentrations and cardiovascular effects of oral oxprenolol in
man. Europ. J. Clin. Pharmacol., 8, 3-9 (1975).
5. Galeazzi, R.L., Benet, L.Z., and Sheiner, L.B. Relationship between the pharmacokinetics and pharmacodynamics of procainamide. Clin. Pharm. Therap., 20, 67-681 (1976).
6. Joubert, P., et al. Correlation between electrocardiographic changes, serum digoxin, and total body digoxin content. Clin.
Pharm. Therap., 20, 676-681 (1976).
7. Amery, A., et al. Relationship between blood level of atenolol and pharmacologic effect. Clin. Pharm. Therap., 21, 691-699
(1977).
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3-10
Pharmacological Response
3.4 Problems
What to do.---> We want to get pharmacokinetic data (elimination rate constant) from pharmacological response data (Response vs concontration and
Response vs time graphs) .
Response vs Time Graph
1. Plot Response vs Time on Cartesian (regular) Graph Paper.
2. Use Response data between 20 and 80 percent of maximum (Pick the straight part) to do the linear regression on. (Rule of thumb: Connect first and last data point with a straight line. If all
the points fall on one side of the line, its not straight!
1.0
Response
0.8
0.6
0.4
0.2
0.0
10
10
10
Time
10
10
10
required). Important: you must determine the best fit line through all of the points that you will
use. Eyeball method: Get the line as close to the points as possible placing as many points
above the line as below the line. Take two points on the line (not data points) to calculate the
change in Y over the change in X.
0.6
0.4
0.2
0.0
10 -810-710 -610-510 -410-310 -210 -1
Response
Response
10010
10
0.8
10 10
10010
1.0
1010
Conc.
Concentration
10
What we are attempting to do is get the logarithm part of the paper on the x axis and have the
numbers get bigger as you go from left to right.
2. Plot concentration on the x axis and response on the y.
3. Find the slope of the line plotted this way by the rise over the run method.
Run is change in ln(C).
If you take any two concentrations such that C2 = 2*C1 then the run is (ln(C2) - ln(C1)).
Using rules of logs, when two logs are subtracted, the numbers are devided, thus: = ln(C2/C1).
If C2 = 2*C1 then ln(C2/C1) = ln(2) = 0.693.
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Pharmacological Response
0.693
Concentration
10
100
1010
110
0
Time
2. Find the slope as before, using semi log paper (Remeber the log is on the Y axis this time, so you
find two concentrations such that c2 = 2*c1 and put it in the rise this time. Thus the slop of the
0.693 = 0.693
line is m = rise
-------- = -------------------------- = k
run
t2 t1
t1
-2
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Pharmacological Response
Oxpranolol
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 0 - 1)
AHFS 00:00.00
GPI: 0000000000
In humans, the pharmacological response to oxpranolol (a beta blocker) is a decrease in beats per minute (bpm) compared to placebo during physical exercise. The following approximate mean data is from 7 healthy volunteers: beats per
minute (bpm) altered with time (t) after oral administration of three doses (D).
TABLE 2-19
Response vs
Concentration
Response vs
time
BPM
Dose (mg)
BPM
Time (hr)
10
40
17.6
13.5
60
13.9
16
80
10.2
19
120
6.6
21
160
Time (min)
C p ng
------
ml
30
699
60
622
120
413
150
292
240
152
360
60
480
24
1. Calculate the half life ( t 1 2 ) of oxpranolol from the pharmacological response table.
2. Plot plasma concentration data on Cartesian graph paper directly as well as transforming Cp into ln C p .
3. Plot plasma concentration data on semilog paper. Use linear regression to find the rate constant of elimination of
oxpranolol.
4. Calculate the half life obtained from the concentration data and compare it with the half life calculation based on the
pharmacological response.
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Pharmacological Response
Minoxidil
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 0 - 2)
AHFS 00:00.00
GPI: 0000000000
Minoxidil is a potent antihypertensive which lowers the mean arterial blood pressure (MAP) in certain patients.
PROBLEM TABLE 0 - 2. Minoxidil
Dose ( mg )
17
2.5
40
5.0
53
7.5
63
10.0
76
15
Time ( hr )
75
20
66
30
56
40
48
50
dR
d ln C
dR
dt
dR-----dt
3. Find the ln(C)oncentration vs. (T)ime slope : ------------- : Note that your slope m = K . If you are having problems
dR
-----------d ln C
understanding this, refer to Sections 2.4.2 -2.4.4. K is the elimination rate constant.
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Pharmacological Response
------------- .
4. Calculate t 1 2 = 0.693
K
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Pharmacological Response
Propranolol
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 0 - 3)
AHFS 00:00.00
GPI: 0000000000
Citation?
Beta blockers can be considered first line drugs of choice in the treatment of hypertension in certain patients. The following data was obtained regarding Propranolol used to treat hypertension in a group of patients.
PROBLEM TABLE 0 - 3. Propranolol
Cp
20
50
16
40
11
30
20
Time (hr)
24
20
19
dR
d ln C
dR
dt
dR
------dt
3. Find the ln(C)oncentration vs. (T)ime slope : ------------- : Note that your slope m = K . If you are having problems
dR
-----------d ln C
understanding this, refer to Sections 2.4.2 -2.4.4.
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Pharmacological Response
------------- .
4. Calculate t 1 2 = 0.693
K
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Pharmacological Response
3.4.1
ANSWERS:
OXPRANOLOL
1. Calculate the half life ( t 1 2 ) of oxpranolol from the pharmacological response table
Oxpranolol
Response (BPM)
22
20
18
16
14
12
10
1
10
10
10
Dose (mg)
TABLE 3.
X
ln(Dose)
Dose
Y
Response
3.689
40
10
13.61
36.89
4.094
60
13.5
16.76
55.27
4.382
80
16
19.20
70.11
4.787
120
19
22.92
90.96
5.075
160
21
25.75
106.58
Y = 79.5
X = 98.25
X = 22.03
XY
XY = 359.82
( X ) = 485.23
( x ) ( y ) ) ( n ( x y ) )m = (-------------------------------------------------------------------2
2
[(x) ] ( n (x ))
y
y = ------ = 15.9
n
X
X = --------- = 4.41
n
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Pharmacological Response
dR = 7.93
----------the slope is equal to the linear regression of the change in response vs. ln concentration.
d ln c
OXPRANOLOL
18
Response (BPM)
16
14
12
10
8
6
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Time (hr)
R R
T1 T 2
16 10
1.45 3.07
dR
dt
1
2
- = --------------------------- = 3.71 therefore, ------- = 3.71 .
The slope of this plot is m = -----------------
dR
------dt = d----------ln c = k = ------------3.71 = 0.4678hr 1
----------dR
dt
7.93
----------d ln c
ln 2 = -------------------------0.693 - = 1.48hr
t 1 2 = -------half life (89 min).
1
k
0.4678hr
2. Plot plasma concentration data on Cartesian graph paper directly as well as transforming Cp into ln C p .
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Pharmacological Response
Oxpranolol
800
3
10
Concentration (ng/mL)
640
Concentration (ng/ml)
480
320
160
10
10
0
0
100
200
300
400
100
500
200
300
400
500
Time (min)
Time (min)
3. Plot plasma concentration data on semilog paper. Use linear regression to find the rate constant of elimination of
oxpranolol.
Using linear regression, as described above, the elimination rate constant is approximately
0.007797 min-1 * (60 min/hr) = 0.4678 hr-1
4. Calculate the half life obtained from the concentration data and compare it with the half life calculation based on the
pharmacological response.
0.693
t 1 2 = ------------------- = 90min = 1.5 hrs compared to 1.48 hours (89 min) from the pharmacological response
0.00763
method.
Basic Pharmacokinetics
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3-20
Pharmacological Response
3.4.2
ANSWERS:
MINOXIDIL
d ln C
R vs Ln(C)
80
60
40
20
0
10
10
10
Dose (mg)
dR = 32.96
-----------d ln C
dR
dt
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3-21
Pharmacological Response
mmH
R vs T
75
70
65
60
55
50
45
20
25
30
35
40
45
50
Time (hr)
dR
------- = 0.91
dt
dR-----dt
3. Find the ln(C)oncentration vs. (T)ime slope : ------------- : Note that your slope m = K .
dR
-----------d ln C
K = 0.028hr
------------0.91 = ( 0.028 )
32.96
4. Calculate t 1 2 = 0.693
------------- .
K
0.693 - = 24.75hr
t 1 2 = ---------------------- 1
0.028hr
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3-22
Pharmacological Response
3.4.3
ANSWERS:
PROPRANOLOL
R vs T
20
15
10
5
0
10
10
dR = 16.36
-----------d ln C
dR
dt
R vs T
25
20
15
10
5
0
dR
------- = 2.93
dt
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3-23
Pharmacological Response
dR-----dt
3. Find the ln(C)oncentration vs. (T)ime slope : ------------- : Note that your slope m = K .
dR
-----------d ln C
K = 0.179hr
------------2.93 = 0.179
16.36
------------- .
4. Calculate t 1 2 = 0.693
K
0.693 - = 3.87hr
t 1 2 = ----------------------
1
0.179hr
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3-24
CHAPTER 4
OBJECTIVES
For an IV one compartment model plasma and urine:
1.
Given patient drug and/or metabolite concentration, amount, and/or rate vs. time
profiles, the student will calculate (III) the relevant pharmacokinetic parameters
available from IV plasma, urine or other excreta data: e.g.
The student will provide professional communication regarding the pharmacokinetic parameters obtained to patients and other health professionals.
3.
The student will be able to utilize computer programs for simulations and data
analysis.
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4-1
PLASMA
Valid equations:
(Obtained from the
LaPlace transforms
derived from the
appropriate models
derived from the
pharmacokinetic
descriptions of the drug)
ln C p = K1 t + ln C p 0
(EQ 4-1)
ln X = K1 t + ln X0
(EQ 4-2)
C p = C p0 e
( )
AUC =
Cp dt
K1t
(EQ 4-3)
DC p 0 = ----Vd
(EQ 4-4)
0.693
t = ------------K
(EQ 4-5)
( Cp n + Cp n + 1 )
Cp last
t + -------------= ------------------------------------2
K1
(EQ 4-6)
0
( )
AUMC =
t C p dt =
Cp last
( t last Cp last )
(EQ 4-7)
K1
Utilization:
Can you determine the
slope and intercept from
a graph? Plot the data
in table 4 -1.on semi-log
graph paper. Extrapolate the line back to time
= 0 to get Cp0. Find the
half life. Calculate the
elimination rate constant.
( t n Cp n ) + ( t n + 1 Cp n + 1 )
MRT = AUMC
-----------------AUC
(EQ 4-8)
Cl = K Vd
(EQ 4-9)
You should be able to plot a data set Concentration vs. time on semilog yielding a straight line
with slope = K1 and an intercept of C p0 .
TABLE 4-1.
Nifedipine 25 mg IV bolus
Time (hr)
Cp
(mcg/L)
139
65.6
31.1
14.6
FIGURE 4-1.
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4-2
FIGURE 4-1.
100
Concentration (ng/mL)
Concentration (mic/L)
10 3
10 2
50
1.85 hr
10 1
0
Time (hours)
Time (hr)
You should be able to determine K1. A plot of the data in TABLE 4-1. results in FIGURE 41. Remember from high school algebra, the slope of any straight line is the rise over the run,
dy
------ , In the case of semi-log graphs dy is the difference in the logarithms of the concentrations.
dx
Thus, using the rules of logarithms, when two logs are subtracted, the numbers themselves are
divided. i.e. ln ( C1 ) ln ( C2 ) = ln C1
------- . Thus if we are judicious in the concentrations that we
C2
take, we can set the rise to a constant number. So, if we take any two concentrations such that
one concentration is half of the other (In FIGURE 4-1. above, we took 100 and 50), the time it
takes for the concentration to halve is the half life (in the graph above, 1.85 hr). Then
1
0.693
0.693
K1 = ------------- = ---------------- = 0.375 hr
t
1.85hr
You should be able to determine V d :. To do this, extrapolate the line to t = 0 . The value of Cp
when t = 0 is C p0 (in the graph above, C p0 = 295 mic
--------- which is equal to D V d for an IV bolus
L
dose only.
Dose
Dose
25mg 1000mic
Thus, Cp 0 = ------------ , V d = ------------- = ------------------ --------------------- = 85L
Vd
Cp 0
295mic
-----------------L
mg
Given any three of the variables of the IV bolus equation, either by direct information (the volume of distribution is such and such) or by graphical data analysis, you should be able to find
the fourth.
You should be able to calculate Area Under the Curve (AUC) from IV Bolus data (Time vs. Cp).
From the above data in TABLE 4-1. the AUC is calculated using (EQ 4-6):
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4-3
()
AUC =
Cp dt
0
Cp n + Cp n + 1 Cp l
= --------------------------------+ -------- which in this case is:
K1
t
Cp 1 + Cp 2
Cp 2 + Cp 3
Cp 3 + Cp last
Cp last
Cp o + Cp 1
t last + -------------- ------------------------- t 1 + ------------------------- t 2 + ------------------------- t 3 + ------------------------------
K1
2
2
2
2
295 + 139
139 + 65.6
65.6 + 31.1
31.1 + 14.6
14.6 mcg
------------------------ 2 + ------------------------- 2 + --------------------------- 2 + --------------------------- 2 + ------------- ----------hr or
2
2
2
2
0.375 L
mcg
mcg
{ 434 + 204.6 + 96.7 + 45.7 + 38.9 } ----------hr = 819.9----------hr . In tabular format, the AUC calculation
L
L
AUC
AUC
t
0
TIME
Cp
295
139
434.0
434.0
65.6
204.6
638.6
31.1
96.7
735.3
14.6
45.7
781.0
38.9
819.9
The AUC of a plot of plasma concentration vs. time, in linear pharmacokinetics, is a number
which is proportional to the dose of the drug which gets into systemic circulation. The proportionality constant, as before, is the volume of distribution. It is useful as a tool to compare the
amount of drug obtained by the body from different routes of administration or from the same
route of administration by dosage forms made by different manufacturers (calculate bioavailability in subsequent discussions).
The AUC of a plot of Rate of Excretion of a drug vs. time, in linear pharmacokinetics, is the
mass of drug excreted into the urine, directly.
You should be able to calculate the AUMC from IV Bolus data (Time vs. Cp). The equation for
AUMC is equation 4-7:
( )
AUMC =
t C p dt =
( t n Cp n ) + ( t n + 1 Cp n + 1 )
Cp last
( t last Cp last )
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4-4
295 + 2 139
2
65.6 + 6 31.1 2 mcg
139 + 4 65.6 2 + 4----------------------------------------- 2 + 2--------------------------------------- 0------------------------------------------------hr +
2
L
2
2
6 31.1 + 8 14.6
8 14.6
14.6 mcg 2
------------------------------------------ 2 + ------------------ + ---------------2- ----------hr or
2
0.375
0.375 L
mcg 2
{ 278 + 540.4 + 449 + 303.4 + 311.47 + 103.82 } = 1986.1----------hr
L
Thus in tabular format the AUMC for data given in TABLE 4-1. is TABLE 4-3 below.
TABLE 4-3 AUMC
Cp*T
AUMC t
AUMC
TIME
Cp
295
139
278
278.0
278.0
65.6
262.4
540.4
818.4
31.1
186.6
449.0
1267.4
14.6
116.8
303.4
1570.8
415.3
1986.1
t
0
The AUMC is the Area Under the first Moment Curve. A plot of T*Cp vs. T is the first
moment curve. The time function buried in this plot, the Mean Residence Time (MRT), can be
extracted using equation 4-8 below.
It is the geometric mean time that the molecules of drug stay in the body. It has utility in the fact
that, as drug moves from the dosage form into solution in the gut, from solution in the gut into
the body, and from the body out, each process is cumulatively additive. That means if we can
physically separate each of these processes in turn, we can calculate the MRT of each process.
The MRT of each process is the the inverse of the rate constant for that process.
You should be able to calculate MRT from IV Bolus data (Time vs. Cp) using equation 4-8
AUMC
1986.1
MRT = ------------------ = ---------------- = 2.42
AUC
819.9
Since there is only the process of elimination (no release of the drug from the dosage form, no
absorption), the MRT is the inverse of the elimination rate constant, K. Thus MRT = 1/K.
Flow Chart 2-1
IV Bolus
MRT(IV) = 1/K
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4-5
Suppose the drug were given in a solution. Then the drug would have to be absorbed and then
eliminated. Since the MRTs are additive, the MRT of the oral solution would be made up of the
MRTs of the two processes, thus:
Flow Chart 2-2
Oral Solution
Ka
Xa
K
X
MRT(os) = MAT(os)+MRT(IV)
MRT(os) =
1/Ka
+ 1/K
Consequently, if a drug has to be released from a dosage form for the drug to get into solution
which is subsequently absorbed, a tablet for example, the MRT of the tablet will consist of the
MRT(IV) and the MAT(os) and the Mean Dissolution Time (MDT), thus:
Flow Chart 2-3
Tablet
Kd
Ka
Xd
Xa
K
X
MRT(tab) = MDT
+ MAT(os)
+ MRT(IV)
MRT(tab) =
1/Kd
1/Ka
1/K
MRT(tab) = MAT(tab)
+ MRT(IV)
1/K
Normally, we dont have information from the oral solution, just IV and tablet. So in that case
the information obtained about absorption from the tablet is bundled together into an apparent
absorption rate constant consisting of both dissolution and absorption.
It should be apparent that this is a reasonably easily utilized and powerful tool used to obtain
pharmacokinetic parameters.
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4-6
4.1.2
1.
2.
ln 2 equation 4-5
t 1 2 = -------K1
3.
1
AUMC
MRT = ------- ( estimate ) MRT = ------------------ equation 4-8
K1
AUC
4.
5.
Cp
Estimate for AUC = AUC = ---------0 which is
K1
()
AUC =
0 Cp dt
( Cp n + Cp n + 1 )
Cp last
Cp dt = ------------------------------------(
t
)
+
-------------
2
K1
AUMC
Cp dt =
( t n Cp n ) + ( t n + 1 Cp n + 1 )
Cp last
( t last Cp last )
K1
V d = Dose
------------- from equation 4-4
Cp 0
8.
Cp 0 Dose Dose
Cl = K1 V d = ----------- ------------- = ------------AUC Cp 0
AUC
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4-7
Acyclovir
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 4 - 1)
De Miranda and Burnette, Metabolic Fate and Pharmacokinetics of the Acyclovir Prodrug Valaciclovir in Cynomolgus Monkeys, Drug Metabolism and Disposition (1994): 55-59.
Acyclovir is an antiviral drug used in the treatment of herpes simplex, varicella zoster, and in suppressive therapy. In
this study, three male cynomolgus monkeys were each given a 10 mg kg intravenous dose. The monkeys weighed an
average of 3.35 kg each. Blood samples were collected and the following data was obtained:
PROBLEM TABLE 4 - 1.
Acyclovir
Serum concentration
Time (hours)
( g mL )
0.167
26.0
0.300
23.0
0.500
19.0
0.75
16.0
1.0
12.0
1.5
7.0
2.0
5.0
From the data presented in the Preceding table, determine the following:
1.
2.
3.
Find MRT .
4.
Find ( C p )0 .
5.
6.
7.
8.
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4-8
(Problem 4 - 1) Acyclovir:
CONCENTRATION (MIC/ML)
10
10
100
0.0
0.5
1.0
1.5
2.0
TIME (HR)
1
1.
k = 0.93hr
2.
t = 0.75hr .
3.
MRT = 1.08hr .
4.
( C p )0 = 30.4ug mL .
5.
AUC = 32.75ug mL hr .
6.
AUMC = 35.2ug mL hr .
7.
V d = 1.1L
8.
Cl = 1.02L hr .
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4-9
Aluminum
(Problem 4 - 2)
AHFS 00:00.00
GPI: 0000000000
Xu, Pai, and Melethil, "Kinetics of Aluminum in Rats. II: Dose-Dependent Urinary and Biliary Excretion", Journal of Pharmaceutical Sciences, Oct 1991, p 946 - 951.
A study by Xu, Pai, and Melethil establishes the pharmacokinetics of Aluminum in Rats. In this study, four rats with an
average weight of 375g, were given an IV bolus dose of aluminum (1 mg/kg). Blood samples were taken at various
intervals and the following data was obtained:
PROBLEM TABLE 4 - 2.
Aluminum
Time (hours)
0.4
19000
0.6
18000
1.4
15000
1.6
14500
2.3
12500
3.0
10500
4.0
8500
5.0
6500
6.0
5000
8.0
3250
10.0
2000
12.0
1250
From the data presented in the preceding table, determine the following:
1.
2.
3.
Find MRT .
4.
Find ( C p )0 .
5.
6.
7.
8.
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4-10
(Problem 4 - 2) Aluminum:
CONCENTRATION (NG/ML)
10
10
10
10
12
TIME (HR)
1.
k = 0.234hr
2.
t = 3hr .
3.
MRT = 4.3hr .
4.
( C p )0 = 21000ng mL .
5.
AUC = 89285ng mL hr .
6.
AUMC = 383926ng mL hr .
7.
V d = 17.86mL
8.
Cl = 4.18mL hr .
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Amgen
(Problem 4 - 3)
AHFS 00:00.00
GPI: 0000000000
Salmonson, Danielson, and Wikstrom, "The pharmacokinetics of recombinant human erythropoetin after intravenous
and subcutaneous administration to healthy subjects", Br. F. clin. Pharmac. (1990), p 709- 713.
Amgen (r-Epo) is a form of recombinant erythropoetin. Erythropoetin is a hormone that is produced in the kidneys and
used in the production of red blood cells. The kidneys of patients who have end-stage renal failure cannot produce
erythropoetin; therefore, r-Epo is being investigated for use in these patients in order to treat the anemia that results
from the lack of erythropoetin. In a study by Salmonson et al, six healthy volunteers were used to demonstrate that
both IV and subcutaneous administration of erythropoetin have similar effects in the treatment of anemia due to
chronic renal failure. The six volunteers were each given a 50 U/kg intravenous dose of Amgen. The average weight
of the six volunteers was 79 kg. Blood samples were drawn at various times and the data obtained is summarized
below:
PROBLEM TABLE 4 - 3.
Amgen
Time (hours)
--------Serum concentration, mU
mL
700
600
400
300
12
150
24
40
From the data presented in the preceding table, determine the following:
1.
2.
3.
Find MRT .
4.
Find ( C p )0 .
5.
6.
7.
8.
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4-12
(Problem 4 - 3) Amgen:
Con (mU/mL)
CONCENTRATION (MU/ML)
103
102
101
0
10
15
20
25
TIME (HR)
1.
k = 0.134hr
2.
t = 5.2hr .
3.
MRT = 7.46hr .
4.
( C p )0 = 900mU mL .
5.
AUC = 6945mU mL hr .
6.
AUMC = 49600 mU mL hr .
7.
V d = 4.44L
8.
Cl = 0.6L hr .
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(Problem 4 - 4)
AHFS 00:00.00
GPI: 0000000000
Brier and Harding, "Pharmacokinetics and Pharmacodynamics of Atrial Naturetic Peptide after Bolus and Infusion Administration in the Isolated Perfused Rat Kidney", The Journal of Pharmacology and Experimental Therapeutics (1989), p 372 - 377.
A study by Brier and Harding a dose of 45 ng was given by IV bolus to rats. Samples of blood were taken at various
intervals throughout the length of the study and the following data was obtained:
PROBLEM TABLE 4 - 4.
Time (minutes)
pg
Serum concentration, -------mL
380
10
280
20
170
30
130
40
100
50
70
60
50
From the data presented in the preceding table, determine the following:
1.
2.
3.
Find MRT .
4.
Find ( C p )0 .
5.
6.
7.
8.
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4-14
(PG/ML)
Con CONCENTRATION
(pg/mL)
ANP
103
102
101
0 10 20 30 40 50 60
Time (min)
1
1.
k = 0.0345min
2.
t = 20.09min .
3.
MRT = 28.95min .
4.
( C p )0 = 386.6pg mL .
5.
6.
7.
V d = 116.4mL
8.
Cl = 4.02mL min .
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Aztreonam
(Problem 4 - 5)
AHFS 00:00.00
GPI: 0000000000
Cuzzolim et al., "Pharmacokinetics and Renal Tolerance of Aztreonam in Premature Infants", Antimicrobial Agents and Chemotherapy (Sept. 1991), p. 1726 - 1928.
Aztreonam is a monolactam structure which is active against aerobic, gram-negative bacilli. The pharmacokinetic
parameters of Aztreonam were established in a study presented in by Cuzzolim et al in which Aztreonam (100 mg/ kg)
was administered intravenously to 30 premature infants over 3 minutes every 12 hours. The group of neonates had an
average weight of 1639.6g. The following set of data was obtained:
PROBLEM TABLE 4 - 5.
Aztreonam
Time (minutes)
40.50
34.99
29.99
23.88
22.20
19.44
16.55
14.99
From the data presented in the preceding table, determine the following:
1.
2.
3.
Find MRT .
4.
Find ( C p )0 .
5.
6.
7.
8.
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4-16
Aztreonam
Con (ug/mL)
CONCENTRATION (UG/ML)
(Problem 4 - 5) Aztreonam:
10 2
10 1
0
TIME (MIN)
1.
k = 0.144min
2.
t = 4.81min .
3.
MRT = 6.94min .
4.
( C p )0 = 45.75ug mL .
5.
6.
7.
V d = 3.58L
8.
Cl = 0.516L min .
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(Problem 4 - 6)
AHFS 00:00.00
GPI: 0000000000
Byatt, et. al., "Serum half-life and in-vivo actions of recombinant bovine placental lactogen in the dairy cow", Journal of Endocrinology (1992), p. 185 - 193.
Bovine placental lactogen (bPL) is a hormone similar to growth hormone and prolactin. It binds to both prolactin and
growth hormone receptors in the rabbit and stimulates lactogenesis in the rabbit. In a study by Byatt, et. al., four cows
(2 pregnant and 2 nonpregnant) were given IV bolus injections of 4 mg and the following data was obtained:
PROBLEM TABLE 4 - 6.
Time (minutes)
-----Serum concentration g
L
3.8
117
6.8
72
12.0
43
16.0
27
20.0
18
From the data presented in the preceding table, determine the following:
1.
2.
3.
Find MRT .
4.
Find ( C p )0 .
5.
6.
7.
8.
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4-18
(MIC/L)
ConCONCENTRATION
(ug/L)
103
102
101
0
10
15
20
Time (min)
1
1.
k = 0.113min
2.
t = 6.13min .
3.
MRT = 8.85min .
4.
( C p )0 = 167.8ug L .
5.
6.
7.
V d = 23.84L
8.
Cl = 2.69L min .
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4-19
Caffeine
(Problem 4 - 7)
AHFS 00:00.00
GPI: 0000000000
Dorrbecker et. al., "Caffeine and Paraxanthine Pharmacokinetics in the Rabbit: Concentration and Product Inhibition Effects.",
Journal of Pharmacokinetics and Biopharmaceutics (1987), p.117 - 131.
This study examines the pharmacokinetics of caffeine in the rabbit. In this study type I New Zealand White rabbits
were given an 8 mg intravenous dose of caffeine. Blood samples were taken and the following data was obtained:
PROBLEM TABLE 4 - 7.
Caffeine
Time (minutes)
g
Serum concentration -------mL
12
3.75
40
2.80
65
2.12
90
1.55
125
1.23
173
0.72
243
0.37
From the data presented in the preceding table, determine the following:
1.
2.
3.
Find MRT .
4.
Find ( C p )0 .
5.
6.
7.
8.
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4-20
(MIC/ML)
ConCONCENTRATION
(ug/L)
(Problem 4 - 7) Caffeine:
101
100
10-1
0
50
Time (min)
1
1.
k = 0.00997min
2.
t = 69.51min .
3.
MRT = 100.3min .
4.
( C p )0 = 4.105ug mL .
5.
6.
7.
V d = 1.95L
8.
Cl = 19.44mL min .
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Ceftazidime
(Problem 4 - 8)
AHFS 00:00.00
GPI: 0000000000
Demotes-Mainard, et. al., "Pharmacokinetics of Intravenous and Intraperitoneal Ceftazidime in Chronic Ambulatory Peritoneal
Dyialysis", Journal of Clinical Pharmacology (1993), p. 475 - 479.
Ceftazidime is a third generation cephalosporin which is administered parenterally. In this study, eight patients with
chronic renal failure were each given 1 g of ceftazidime intravenously. Both blood samples were taken the data
obtained from the study is summarized in the following table:
PROBLEM TABLE 4 - 8.
Ceftazidime
Time (hours)
mg
Serum concentration ------L
50
45
38
24
21
36
14
48
11
60
72
From the data presented in the preceding table, determine the following:
1.
2.
3.
Find MRT .
4.
Find ( C p ) 0 .
5.
6.
7.
8.
Basic Pharmacokinetics
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4-22
CONCENTRATION (MG/L)
Con (mg/L)
(Problem 4 - 8) Ceftazidime:
10 2
10 1
10 0
0
20
40
60
80
Time (hours)
1
1.
k = 0.0324hr
2.
t = 21.39hr .
3.
MRT = 30.86hr .
4.
( C p )0 = 47.57mg L .
5.
AUC = 1468.2mg L hr .
6.
AUMC = 45308.6mg L hr .
7.
V d = 21.02L
8.
Cl = 0.681L hr .
Basic Pharmacokinetics
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4-23
Ciprofloxacin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 4 - 9)
AHFS 00:00.00
GPI: 0000000000
Lettieri, et. al., "Pharmacokinetic Profiles of Ciprofloxacin after Single Intravenous and Oral Doses", Antimicrobial Agents and
Chemotherapy (May 1992), p. 993 -996.
Ciprofloxacin is a fluoroquinolone antibiotic which is used in the treatment of infections of the urinary tract, lower respiratory tract, skin, bone, and joint. In this study, twelve healthy, male volunteers were each given 300 mg intravenous
doses of Ciprofloxacin. Blood and urine samples were collected at various times throughout the day and the following
data was collected:
PROBLEM TABLE 4 - 9.
Ciprofloxacin
Time (hours)
mg
Serum concentration ------L
1.20
0.85
0.70
0.50
0.35
10
0.25
From the data presented in the preceding table, determine the following:
1.
2.
3.
Find MRT .
4.
Find ( C p )0 .
5.
6.
7.
8.
Basic Pharmacokinetics
REV. 99.4.25
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4-24
CONCENTRATION (MG/L)
Con (mg/L)
(Problem 4 - 9) Ciprofloxacin:
101
100
10-1
0
10
Time (hours)
1
1.
k = 0.1875hr
2.
t = 3.7hr .
3.
MRT = 5.33hr .
4.
( C p )0 = 1.57mg L .
5.
AUC = 8.395mg L hr .
6.
AUMC = 44.74mg L hr .
7.
V d = 190.6L
8.
Cl = 35.74L hr .
Basic Pharmacokinetics
REV. 99.4.25
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4-25
(Problem 4 - 10)
AHFS 00:00.00
GPI: 0000000000
Nadai et al, "Pharmacokinetics and the Effect of Probenecid on the Renal Excretion Mechanism of Diprophylline", Journal of
Pharmaceutical Sciences (Oct 1992), p. 1024 - 1027.
Diprophylline is used as a bronchodilator. A study by Nadai et al was designed to determine whether or not coadministration of Diprophylline with Probenecid affected the pharmacokinetic parameters of Diprophylline. In this study,
male rats (average weight: 300 g) were given 60 mg/kg of Diprophylline intravenously and a 3 mg/kg loading dose of
Probenecid followed by a continuous infusion of 0.217 mg/min/kg of Probenecid. The following set of data was
obtained for Diprophylline (DPP):
Time (minutes)
g
Serum concentration -------mL
16
40.00
31
27.00
60
13.00
91
6.50
122
3.50
From the data presented in the preceding table, determine the following:
1.
2.
3.
Find MRT .
4.
Find ( C p )0 .
5.
6.
7.
8.
Basic Pharmacokinetics
REV. 99.4.25
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4-26
CONCENTRATION (MIC/ML)
Con (ug/mL)
102
10 1
100
0
20
40
60
80
100
Time (min)
1
1.
k = 0.023min
2.
t = 30.13min .
3.
MRT = 43.48min .
4.
( Cp ) 0 =
5.
6.
7.
V d = 326.5mL
8.
Cl = 7.5mL min .
55.13ug mL .
Basic Pharmacokinetics
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4-27
Epoetin
(Problem 4 - 11)
AHFS 00:00.00
GPI: 0000000000
MacDougall et. al., "Clinical Pharmacokinetics of Epoetin (Recombinant Human Erythropoetin", Clinical Pharmacokinetics
(1991), p 99 - 110.
Epoetin is recombinant human erythropoetin. Erythropoetin is a hormone that is produced in the kidneys and used in
the production of red blood cells. The kidneys of patients who have end-stage renal failure cannot produce erythropoetin; therefore, Epoetin is used in these patients to treat the anemia that results from the lack of erythropoetin. Epoetin
has also been used in the treatment of anemias resulting from AIDS. malignant disease, prematurity, rheumatoid arthritis, sickle-cell anemia, and myelosplastic syndrome. In a study by Macdougall et al, eight patients who were on peritoneal dialysis (CAPD) were given an IV bolus dose of 120 U/kg which decayed monoexponentially from a peak of 3959
U/L to 558 U/L at 24 hours. The following data was obtained:
PROBLEM TABLE 4 - 11.
Epoetin
Time (hours)
U
Serum concentration ---L
0.0
4000
0.5
3800
1.0
3600
2.0
3300
3.0
3000
4.0
2550
5.0
2350
6.0
2150
7.0
1900
From the data presented in the preceding table and assuming that the patient weighs 65 kg, determine the following:
1.
2.
3.
Find MRT .
4.
Find ( C p ) 0 .
5.
6.
7.
8.
Basic Pharmacokinetics
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4-28
Con (U/L)
CONCENTRATION (U/L)
104
103
0
Time (hours)
1
1.
k = 0.107 hr
2.
t = 6.5 hr .
3.
MRT = 9.38 hr .
4.
( Cp) 0
5.
Units hr
AUC = 37775-----------------------.
L
6.
hr
AUMC = 354697Units
-------------------------- .
L
7.
V d = 1.9 L
8.
L
Cl = 0.2065 ----.
hr
= 4023 Units/L .
Basic Pharmacokinetics
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4-29
Famotidine
(Problem 4 - 12)
AHFS 00:00.00
GPI: 0000000000
Kraus, et. al., "Famotidine--Pharmacokinetic Properties and Suppression of Acid Secretion in Pediatric Patients Following Cardiac Surgery", Clinical Pharmacokinetics (1990), p 77 - 80.
Famotidine is a histamine H2-receptor antagonist. The study by Kraus, et. al., focuses on the kinetics of famotidine in
children. In the study, ten children with normal kidney function and a body weight ranging from 14 - 25 kg, were each
given a single intravenous 0.3 mg/kg dose of famotidine. Blood and urine samples were taken providing the following
data:
PROBLEM TABLE 4 - 12.
Famotidine
Time (hours)
g
Serum concentration -----L
0.33
300
0.50
250
1.00
225
4.00
125
8.00
70
12.00
40
16.00
15
From the data presented in the preceding table, determine the following assuming that the patient weighs 17.2 kg:
1.
2.
3.
Find MRT .
4.
Find ( C p ) 0 .
5.
6.
7.
8.
Basic Pharmacokinetics
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4-30
(MIC/L)
ConCONCENTRATION
(ug/mL)
10 3
10 2
10 1
0
10
15
20
Time (hours)
1
1.
k = 0.17 hr
2.
t = 3.9 hr .
3.
MRT = 5.7 hr .
4.
( Cp ) 0 =
5.
6.
g hr
AUMC = 9000-----------------.
L
7.
V d = 18 L
8.
Cl = 3.2L .
g
285-----.
L
Basic Pharmacokinetics
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4-31
Ganciclovir
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 4 - 13)
AHFS 00:00.00
GPI: 0000000000
Trang, et. al., "Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections", Clinical Pharmacology and Therapeutics (1993), p. 15 - 21.
Ganciclovir (mw: 255.23) is used against the human herpes viruses, cytomegalovirus retinitis, and cytomegalovirus
infections of the gastrointestinal tract. In this study, twenty-seven newborns with cytomegalovirus disease were given
4 mg/kg of ganciclovir intravenously over one hour. Blood samples were taken and the data obtained is summarized in
the following table:
Ganciclovir
Time (hours)
Serum concentration
1.50
4.50
2.00
4.00
3.00
3.06
4.00
2.40
6.00
1.45
8.00
0.87
From the data presented in the preceding table and assuming the patient weighs 3.6 kg, determine the following :
1.
2.
3.
Find MRT .
4.
Find ( C p ) 0 .
5.
6.
7.
8.
Basic Pharmacokinetics
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4-32
CONCENTRATION (MICMOLE/L)
10
10
10
0
TIME (HR)
1
1.
k = 0.288hr
2.
t = 2.4hr .
3.
MRT = 3.5hr .
4.
( Cp ) 0 =
5.
mole hr
AUC = 80 -------------------------.
mL
6.
mole23 --------------.
mL
7.
8.
1000 g4 mg
------- 3.6kg -----------------kg
mg - = 2.45L
V d = Dose
------------- = -----------------------------------------------------------Cp 0 23 ---------------mole 255.23 --------------g
L
mole
L .
Cl = 0.7 ----hr
Basic Pharmacokinetics
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4-33
Imipenem
(Problem 4 - 14)
AHFS 00:00.00
GPI: 0000000000
Heikkila, Renkonen, and Erkkola, "Pharmacokinetics and Transplacental Passage of Imipenem During Pregnancy", Antimicrobial
Agents and Chemotherapy (Dec. 1992), p 2652 - 2655.
Imipenem is a beta-lactam antibiotic which is used in combination with cilastin and is active against a broad spectrum
of bacteria. The pharmacokinetics of Imipenem in pregnant women is established in this study. Twenty women (six of
which were non-pregnant controls) were given a single intravenous dose of 500 mg of imipenem-cilastin (1:1). Blood
samples were taken at various intervals and the data obtained is summarized in the following table:
Imipenem
Time (minutes)
mg
Serum concentration ------L
10
27.00
15
23.50
30
15.50
45
9.50
60
6.50
From the data presented in the preceding table, determine the following:
1.
2.
3.
Find MRT .
4.
Find ( C p ) 0 .
5.
6.
7.
8.
Basic Pharmacokinetics
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4-34
CONCENTRATION (MG/L)
10
10
10
10
20
30
40
50
60
TIME (MIN)
1
1.
k = 0.029 min
2.
t = 24 min .
3.
4.
( Cp) 0=
5.
min
AUC = 1250mg
--------------------.
L
6.
min
AUMC = 43125mg
----------------------- .
L
36.2 mg
------- .
L
7.
8.
500mg = 13.8L
Vd = Dose
------------- = -----------------Cp 0 36.2mg
------L
L
Cl = 0.4 --------.
min
Basic Pharmacokinetics
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4-35
Methylprednisolone
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 4 - 15)
AHFS 00:00.00
GPI: 0000000000
Patel, et. al., "Pharmacokinetics of High Dose Methylprednisolone and Use in Hematological Malignancies", Hematological
Oncology (1993), p. 89 - 96.
Methylprednisolone is a corticosteriod that has been used in combination chemotherapy for the treatment of hematological malignancy, myeloma, and acute lymphoblastic leukemia. In a study by Patel et. al., eight patients were given
1.5 gram intravenous doses of methylprednisolone from which the following data was obtained:
Methylprednisolone
Time (hours)
g
Serum concentration ------mL
0.5
19.29
1.0
17.56
1.8
15.10
4.0
9.98
5.8
7.10
8.0
4.70
12.0
2.21
18.0
0.71
24.0
0.23
From the data presented in the preceding table, determine the following:
1.
2.
3.
Find MRT .
4.
Find ( C p ) 0 .
5.
6.
7.
8.
Basic Pharmacokinetics
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4-36
CONCENTRATION (MIC/ML)
102
101
Con (ug/mL)
100
10-1
0
10
15
20
25
Time (hours)
1
1.
k = 0.188 hr
2.
t = 3.69hr .
3.
MRT = 5.3hr .
4.
( Cp) 0=
5.
6.
g hr
AUMC = 598.4-----------------.
mL
7.
V d = 71L
8.
L
Cl = 13.3 ----.
hr
g
21.2 -------.
mL
Basic Pharmacokinetics
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4-37
Omeprazole
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 4 - 16)
AHFS 00:00.00
GPI: 0000000000
Anderson, et. al., "Pharmacokinetics of [14C] Omeprazole in Patients with Liver Cirrhosis", Clinical Pharmacokinetics (1993), p.
71 - 78.
Omeprazole (mw: 345.42) is a gastric proton-pump inhibitor which decreases gastric acid secretion. It is effective in
the treatment of ulcers and esophageal reflux. In normal patients 80% of the omeprazole dose is excreted as metabolites in the urine and the remainder is excreted in the feces. In the study by Anderson, et. al., eight patients with liver
cirrhosis were given 20 mg, IV bolus doses of omeprazole. The patients had a mean body weight of 70 kg. Both blood
were taken at various intervals throughout the study and the following data was obtained:
Omeprazole
Time (hours)
mole
Serum concentration ---------------mL
0.75
3.49
1.00
3.25
2.00
2.46
3.00
1.86
4.00
1.40
5.00
1.06
6.00
0.80
7.00
0.61
8.00
0.46
10.00
0.26
12.00
0.15
From the data presented in the preceding table, determine the following :
1.
2.
3.
Find MRT .
4.
Find ( C p ) 0 .
5.
6.
7.
8.
Basic Pharmacokinetics
REV. 99.4.25
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4-38
Omeprazole
CONCENTRATION (PICOMOLE/ML)
Con (umol/mL)
101
100
10 -1
0
10 12
Time (hours)
1.
k = 0.280hr
2.
t = 2.5hr .
3.
MRT = 3.57hr .
4.
( Cp ) 0 =
5.
mole hr
AUC = 15.4 -------------------------.
mL
6.
mole
4.3 ---------------.
mL
7.
8.
Dose- = -----------------------------------------------------------------------------------------------------------20mg
Vd = -----------= 13465L
Cp 0 4.3 -------------- mole
mmole
345.42mg
1000mL
- ------------------------- ------------------------ -------------------mL 109 mole mmole
L
L
Cl = 3.9 ----.
hr
Basic Pharmacokinetics
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4-39
Pentachlorophenol
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 4 - 17)
AHFS 00:00.00
GPI: 0000000000
Reigner, Rigod, and Tozer, "Absorption, Bioavailability, and Serum Protein Binding of Pentachlorophenol in the B6C3F1 Mouse",
Pharmaceutical Research (1992), p 1053 - 1057.
Pentachlorophenol (PCP) is a general biocide. That is, it is an insecticide, fungicide, bactericide, herbicide, algaecide,
and molluskicide, that is used as a wood preservative. Extensive exposure to PCP can be fatal. In a study by Reigner
et al, six mice (average weight: 27 g) were given 15 mg/kg of PCP by intravenous bolus. Blood samples were taken at
various intervals from which the following data was obtained:
PROBLEM TABLE 4 - 17.
Pentachlorophenol
Time (hours)
g
Serum concentration ------mL
0.083
38.00
4.000
22.00
8.000
14.00
12.000
7.90
24.000
1.30
28.000
0.75
32.000
0.60
36.000
0.40
From the data presented in the preceding table, determine the following :
1.
2.
3.
Find MRT .
4.
Find ( C p ) 0 .
5.
6.
7.
8.
Basic Pharmacokinetics
REV. 99.4.25
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4-40
CONCENTRATION (MIC/ML)
102
101
Con (ug/mL)
100
10-1
0
10
20
30
40
Time (hours)
1
1.
k = 0.134 hr
2.
t = 5.2hr .
3.
MRT = 7.5hr .
4.
g- .
( C p ) 0 = 35.6 ------mL
5.
g hr
AUC = 281 ----------------- .
mL
6.
hr - .
AUMC = 2100g
-----------------mL
7.
V d = 11.4mL
8.
Cl = 1.5 ml
------ .
hr
Basic Pharmacokinetics
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4-41
9-(2-phophonylmethoxyethyl) adenine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 4 - 18)
AHFS 00:00.00
GPI: 0000000000
Naesens, Balzarini, and Clercq, "Pharmacokinetics in Mice of the Anti-Retrovirus Agent 9-(2-phophonylmethoxyethyl) adenine",
Drug Metabolism and Disposition (1992), p. 747- 752.
9-(2-phophonylmethoxyethyl) adenine
Time (minutes)
g
Serum concentration -------mL
2.0
90.3
2.9
83.9
5.6
67.3
8.9
51.5
10.5
45.2
13.5
35.4
15.0
31.3
20.0
20.9
24.0
15.1
59.6
0.9
From the data presented in the preceding table, determine the following. (Assume that the mouse weighs 200g.)
1.
2.
3.
Find MRT .
4.
Find ( C p )0 .
5.
6.
7.
8.
Basic Pharmacokinetics
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4-42
(MIC/ML)
ConCONCENTRATION
(ug/mL)
102
101
100
10 -1
0
10 20 30 40 50 60
Time (min)
1
1.
k = 0.08min
2.
t = 8.67min .
3.
MRT = 12.5min .
4.
g( C p ) 0 = 105 ------.
mL
5.
hr- .
AUC = 1300 g
---------------mL
6.
hr .
AUMC = 16250g
------------------mL
7.
V d = 47.6ml
8.
mL
Cl = 3.8 --------.
min
Basic Pharmacokinetics
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4-43
Thioperamide
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 4 - 19)
AHFS 00:00.00
GPI: 0000000000
Sakurai, et. al., "The Disposition of Thioperamide, a Histamine H3-Antagonist, in Rats", J. Pharm. Pharmacol. (1994), p. 209 212.
Thioperamide is a histamine (H3) receptor-antagonist. In a study by Sakurai et al, rats were given 10 mg/kg intravenous injections of Thioperamide. The following data was obtained from the study:
PROBLEM TABLE 4 - 19.
Thioperamide
Time (minutes)
g
Serum concentration -------mL
3.7
3.1
7.5
2.8
13
2.4
45
1.1
60
0.74
120
0.16
From the data presented in the preceding table, determine the following:
1.
2.
3.
Find MRT .
4.
Find ( C p )0 .
5.
6.
7.
8.
Basic Pharmacokinetics
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4-44
(MIC/ML)
ConCONCENTRATION
(ug/mL)
101
100
10-1
0
20
40
60
80 100 120
Time (min)
1
1.
k = 0.0254min
2.
t = 27.3min .
3.
MRT = 39.4min .
4.
g
( C p )0 = 3.39 -------.
mL
5.
minAUC = 133.5 g
-------------------.
mL
6.
7.
10 mg
------Dose
kg
LVd = ------------- = ------------------------------------------------------------------- = 2.95 ----Cp 0 3.39 ------g- -----------------mg - 1000mL
kg
-------------------mL 1000g
L
8.
Cl = 0.0254min
Basic Pharmacokinetics
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4-45
Cocaine
(Problem 4 - 20)
Khan,vM. et. al. Determination of pharmacokinetics of cocaine in sheep by liquid chromatography J. Pharm. Sci. 76:1 (39-43)
Jan 1987
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4-46
4.1.3
URINE
From the Laplace Transform of a drug given by IV bolus we find that :
ku
( K1 t )
X u = ------ X0 ( 1 e
)
K1
(EQ 4-10)
(EQ 4-11)
ku
-X
where the amount of drug that shows up in the urine at infinite time, ( Xu ) = -----K1 0 .
Thus a plot of ( Xu ) X u vs. time on semi-log paper would result in a straight line
with a slope of -K1 and an intercept of ( Xu ) .. and we can get ku from the intercept
( X u )
k u = K 1 -------------X0
This
Time (hr)
Cumulative
Enalapril in urine
(mg)
0.41
0.59
0.65
0.35
0.80
0.20
0.88
0.12
0.96
0.04
1.0
------
X u mg
Basic Pharmacokinetics
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4-47
Utilizations: A.R.E.
Method
FIGURE 4-2.
10
Xu(inf) - Xu
0.2
0.1
-1
10
1.3 hr
half life
-2
10
Hours
You should be able to transform a data set containing amount of drug in the urine vs. time into
cumulative amount of drug in the urine vs. time and plot the ARE. (Amount Remaining to be
Excreted ->
K1 = 0.533 hr
and an intercept of
ku X0
( X u ) = --------------= 1.0 mg
K1
You should be able to determine the elimination rate constant, K1, from cumulative urinary
excretion data. (Calculate the slope of the graph on SL paper.)
You should be able to determine the excretion rate constant, ku, from cumulation urinary excretion data. (Divide the intercept of the graph by X0 and multiply by K1.
( X u )
1 1.0 mg
1
k u = K 1 -------------= 0.53 hr ----------------- = 0.106 hr )
X0
5.0 mg
km
ku
------ 100 and percent excreted unchanged = ------ 100 assuming
K1
K1
K = k u + km
A second method is to plot the rate at which the drug shows up in the urine over
time. Again, using the LaPlace transforms, we find that:
Utilization: Rate of
excretion method
dX u
K1 t
K1 t
--------- = k u X0 e
= R0 e
(EQ 4-12)
dt
Thus, a plot of the rate of excretion vs. time results in a straight line on semi-log
paper with a slope of -K1 and an intercept, R0 , of kuX0 . Rearranging the intercept
Basic Pharmacokinetics
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4-48
equation yields
rate
dXu
dt
R
k u = -----0- .
X0
X u
---------- ,
t
that means to our calculations is that over the interval of data collection, the total
amount of drug collected divided by the total time interval is the average rate. In
the beginning of the interval the rate was faster than at the end of the interval. So
the average rate must have occurred in the middle of the interval. Thus equation 412 which is the instantaneous rate can be rewritten to
X u
K1 t mid
K1 t mid
---------- = k u X0 e
= R0 e
t
TABLE 4-5 Enalapril
(EQ 4-13)
Interval (hr)
t(mid)
Enalapril in
urine X u ,(mg)
0-1
0.5
0.41
0.41
1-2
1.5
0.24
0.24
2-3
2.5
missed sample
3-4
3.5
0.08
0.08
4-6
0.08
0.04
You should be able to transform a data set containing amount of drug in the urine vs. time interX
-1
0
10
R0 = 0.53 mg/hr
-2
-1
10
1.3 hr
half life
-2
10
T (Mid)
You should be able to determine k u extrapolate the line to t = 0 . The value of Rate (at
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R
1
0.53mg/hr
- = 0.106hr
Thus, -----0- = -----------------------X0
5mg
The rate equation is superior clinically because the ARE method requires collection of all of the urine which is usually only possible when you have a catheterized
patient while the Rate Method does not. (People dont urinate on command, and
your data could be in the toilet, literally.)
An additional advantage of the rate equations is that the
AUC
mass, which gives the total amount of drug excreted into the urine directly. Thus:
AUC
R
mg/hr = 1 mg
= -------0 = 0.53
-------------------------1
K1
0
0.53 hr
where ku is the rate constant through which the drug entered the urine and
K1 t
dX
------- = X 0 e
dt
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4.2 Metabolite
4.2.1
PLASMA
Remember, the LaPlace Transform of the metabolite data yielded
( km Xo )
( km Xo )
K 2t
K 1t
K 1t
K2t
X m = ------------------------ (e
e
) or Xm = ------------------------ (e
e
) depending
( K1 K2 )
( K2 K1 )
on which rate constant that we arbitrarily assigned to be K1, the summation of all
the ways that the drug is removed from the body and K2, the summation of all the
ways that the metabolite is removed from the body. When we begin to manipulate
the data, we know that we have a curve with two different exponents in it. (If they
were the same, the equation would be different.) We dont know which is bigger,
K1 or K2, but we can rewrite the equation to simply reflect Klarge and Ksmall,
knowing that one is K1 and the other is K2 but not which is which. If we, then,
devided both sides of the equation by Vdm, the volume of distribution of the
metabolite, we would get :
km
X0 ( Ksmall t ) ( K l arg e t )
- e
e
C pm = ------------------------------------- --------
K l arg e K small V dm
Utilization:
Curve Stripping
(EQ 4-14)
You should be able to plot a data set of plasma concentration of metabolite vs. time on semi-log
paper yielding a bi-exponential curve.
Kt
0 as t . And e
K l arg e t
k l arg e t
K small t
time, t, e
. In fact
e
time, t, the equation becomes :
0 faster than e
K l arg e t
k small t
km
X0 ( Ksmall t )
C pm = ---------------------------------- --------(e
)
K
K
V
l arg e
small
(EQ 4-15)
dm
So that the plot of the terminal portion of the graph would yield a straight line with a slope of
-Ksmall and an intercept of I =
km
X0
--------------------------------- --------K
V
K
l arg e
small
dm
You should be able to obtain the slope of the terminal portion of the curve, the negative of
which would be the smaller of the two rate constants, K small , (either the summation of all the
ways that the drug is eliminated,
eliminated,
K2 ).
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km
X 0 ( K big t )
C pm C pm = ---------------------------------- --------(e
)
K l arg e K small Vdm
(EQ 4-16)
which is a straight line on semi-log paper with a slope of -kbig and an intercept of
km
X0
--------I = -----------------------------------. Note: we can get the larger of the two rate constants from this
K
V
K
l arg e
small
dm
method.
TABLE 4-6
Drug
Metabolite
(1)
(2)
(3)
(4)
Time (hr)
Cp
(mcg/L)
Cpm1 (mcg/L)
Cpm
(5)
Cpm
Cpm
181.2
181.2
0.5
24.7
175
150.3
44.4
168.9
124.5
139
71.8
157.5
85.7
65.6
96.5
136.9
40.4
31.1
100
119
19
14.6
94.7
12
76.5
24
34
In the above data Cp vs. Time is the plasma profile of the drug from Table 4-1 on page 2 and
Cpm1 vs. Time is the plasma profile of the metabolite. A plot of Cp vs. Time yielded a straight
line with a slope,(-K1) of -0.375 hr-1,
mic/L,
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10 3
Concentration (mic/L)
100
Concentration (ng/mL)
10 2
50
1.85 hr
10 1
0
Time (hours)
Time (hr)
while a plot of Cpm1 vs. Time( Figure 4-3 on page 53) yields a biexponential plot with a terminal slope of 0.07 hr-1 , k small = 0.693
------------- and extrapolating the terminal line back to time = 0
10 hr
L)
Concentration (mic/L)
103
mic
Cpm0 = 181 --------L
80
102
40
10 hr
101
0
12
16
20
24
Time (hours)
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You should be able to feather (curve strip) the other rate constant out of the data by plotting the
difference between the extrapolated (to t = 0 ) terminal line (column 4 vs. 1 in Table 4-6 on
page 52) and the observed data (at early times) (column 3 vs. 1 in Table 4-6 on page 52) yielding a straight line with the slope of the line equal to the negative of the other (larger) rate constant (column 5 vs. 1 in Table 4-6 on page 52).
First you would fill in the Cpm column (column 4 in Table 4-6 on page 52) by computing Cpm
for various values of time i.e Cpm = Cpm0 e
ks m a l l t
graph. Then Cpm Cpm (column 5 in Table 4-6 on page 52) would be column 4 - column 3.
Then a plot of Cpm Cpm vs. time (column 5 vs. 1 in Table 4-6 on page 52) is shown below.
FIGURE 4-4.
10
Intercept
Column 5
100
102
1.85 hr
50
Half life
1
10
Time (hr)
In this case, the slope of the stripped line line is -0.375 hr-1 and the intercept is 0.181.2 mic/L.
The slope of -0.375 hr-1 should not be surprising as the plot of the data in Figure 4-3 on page 53
resulted in a terminal slope of -.07 hr-1 . Since the data set yielded a bi-exponential plot, separating out the exponents could only yield K1 (0.375 hr-1) or K2 as determined by our Laplace
Transform information. Thus, the terminal slope could be either -K1 or -K2. Since it was obviously not -K1, it had to be -K2. Thus the other rate constant obtained by stripping has to be K1.
You can determine which slope is which rate constant if you have any data regarding intact drug
(i e. either plasma or urine time profiles of intact drug) as the slope of any of those profiles is
always
K1 .
You should be able to determine V dm if you have any urine data regarding intact drug (i.e.
urine time profiles of intact drug) as the intercept of those profiles allow for the solution of k m .
Thus the intercept, I, of the extrapolated line of equation 4-14 could be rearranged to contain
only one unknown variable, V dm
1
mic
0.375hr 25mg 1000
---------------------km X0
mg
= ----------------------------------------------- = -------------------------------------------------------------------------- = 170 L .
1
( K l arg e K small ) I
mic
( 0.375 0.07 ) hr 181.2--------L
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Utilization:
MRT Calculations
You should be able to determine the rate constants using MRT calculations.
In a caternary chain, each compartment contributes its MRT to the overall MRT of the drug,
thus:
Flow Chart 2-4
IV Bolus
K1
MRT(IV) = 1/K1
Suppose the drug were given by IV bolus. Then the drug would have to be metabolized and the
metabolite eliminated. Since the MRTs are additive, the overall MRT of the metabolite would
be made up of the MRTs of the two processes, thus:
Flow Chart 2-5
Metabolite
km
kmu
Xm
MRT(met) = MRT(elim)+MRT(IV)
MRT(met) =
1/K2
+ 1/K1
Thus, using the data from Table 4-3 on page 5 the MRT(IV)Trap is
AUMC
1986.1
AUMC
2100
MRT = ------------------ = ---------------- = 2.42 hr or about MRT = ------------------ = ------------ = 2.67 hr using calculus.
AUC
819.9
AUC
787
And using the data from columns 1 and 3 from Table 4-6 on page 52 the MRT(met) using calcuAUMC- = 36000
lus is MRT = ------------------------------- = 17 hr.
AUC
2116
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4.2.2
URINE
Valid equations:
dX mu
k mu k m X0
K
t
K
t
------------- = --------------------------------------- { e small e l arg e }
dt
( K l arg e K small )
Utilization:
(EQ 4-17)
as in the previous urinary rate equation, clinically we work with the average rate
over a definite interval which results in rewriting equation 4-17 as:
Xmu
k mu k m X0
K
t
K
t
------------= --------------------------------------- { e small mid e l arg e mid }
t
( K l arg e K small )
(EQ 4-18)
You should be able to plot a data set of rate of metabolite excreted vs. time (mid) on semi-log
paper yielding a bi-exponential curve.
You should be able to obtain the slope of the terminal portion of the curve, the negative of
which would be the smaller of the two rate constants (either
K1 or K2 ).
You should be able to feather (curve strip) the other rate constant out of the data by plotting the
difference between the extrapolated (to t = 0 ) terminal line and the observed data (at early
times) yielding a straight line with the slope of the line equal to the negative of the other (larger)
rate constant (either
K1 or K2 ).
K1 .
By this time, it should be apparent that data which fits the same shape curve
(mono-exponential, bi-exponential, etc.) are treated the same way. When the
curves are evaluated, the slopes and intercepts are obtained in the same manner.
The only difference is what those slopes and intercepts represent. These representations come from the equations which come from the LaPlace Transforms which
come from our picture of the pharmacokinetic description of the drug. Please
refer back to the section on graphical analysis in the Chapter 1, Math review for a
interpretation of slopes and intercepts of the various graphs.
Temporarily, please refer to exam section 1, chapter 14 for problems for this section (until problems can be generated) as well as additional problems for the previous sections.
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CHAPTER 5
I.V. Infusion
OBJECTIVES
1.
Given patient drug concentration and/or amount vs. time profiles, the student will
calculate (III) the relevant pharmacokinetic parameters available ( V d , K, k m , k r ,
AUC ,
2.
3.
4.
5.
6.
7.
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I.V. Infusion
PLASMA
Valid equations:
Kt
Q
C p = -------------( 1 e ) or
K Vd
(EQ 5-1)
Kt
Dose
C p = --------------------------------------( 1 e )
K Vd T infusion
(EQ 5-2)
Q
( C p )ss = -------------K Vd
(EQ 5-3)
C p = C p( term ) e
Kt
(EQ 5-4)
Rewriting equation 5-4 to an equation which may be used by a computer results in:
Q - ( e K T e K T )
Cp = ----------KV
where
T = ( T T i v )
and
T = 0
(EQ 5-5)
for ( T > T iv )
for ( T < T iv )
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I.V. Infusion
Using The Scientist@s Unit function makes the change in T straight forward. In
The Scientist@, Unit(+) = 1 and Unit(-) = 0, so defining T = ( T T iv ) UNIT ( T Ti v )
meets these needs.
This equation is utilized in The Scientist@s companion product PKAnalyst@ also
by MicroMath. Since the route of administration is an infusion and we would
know how much we gave (Dose), how fast we gave it (Q), and over how long the
infusion lasted (Tiv), the only other variables in the equation are K and Vd. PKAnalyst asks for Tiv and yields DoverV ( Dose
------------- ) and K as parameters resulting from
Vd
non-linear regression analysis. Dividing Dose by Dose
------------- yields Vd.
Vd
Utilization:
You should be able to determine the infusion rate necessary to obtain a desired
plasma concentration. Rearranging equation 5-3 results in:
K V d ( C p )ss = Q
(EQ 5-6)
You should be able to determine how long it would take to get to a desired plasma
concentration. Using equation 5-1 and equation 5-3, it looks like it will take forever to get exactly to steady state because in order for
Q = -------------Q ( 1 e Kt ) , e Kt 0 which occurs when t = . So,
( C p )ss = -------------K Vd
K Vd
how close is close enough? If ( C p ) = 0.95 ( C p )ss , thats good enough in most
peoples estimation. So in order to find out how long it will take we use equation
5-1, setting ( C p ) = 0.95 ( C p )ss and solve for time. Thus:
Q ( 1 e Kt ) which results in
( C p ) = 0.95 ( C p )ss = -------------K Vd
0.95 = ( 1 e
Kt
0.95 1 = e
Kt
ln ( 0.05 ) = Kt
2.996 = Kt
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I.V. Infusion
---------------2.996 = t
K
2.996
-------------t 1--- = 4.32t 1--- = t ,
0.693 2
2
(EQ 5-7)
or about 4.32 half lives to get to 95% of steady state. Generalizing, then, the number of half-lives it takes to get to steady-state is equal to the logarithm of the
inverse of how close is close (in this case, 5% or 0.05 = 20) devided by the logarithm of two.
Changing infusion rates:
(EQ 5-8)
Assuming equilibrium was reached at infusion rate Q1, we could simplify equation
5-8 by setting T = 0 at the time of the rate change (thus we would be interested in
the time after the change) resulting in:
k T
k T
Q1
Q2
Cp = -----------e
+ ------------ ( 1 e
)
KV
KV
(EQ 5-9)
Under these conditions, it would be useful to determine the time to reach the new
equilibrium. As before, within 5% is close enough. Thus if we are coming down
Q2- and if we were
(lowering the Cp, i.e. Q2 < Q1), we would want Cp = 1.05 ----------KV
Q2 . Taking
going up (raising the Cp, i.e. Q2 > Q1), we would want Cp = 0.95 ----------KV
the first condition we find:
k T
Q2
Q1
Q2 - ( 1 e k T )
+ ----------Cp = 1.05 ------------ = ------------ e
KV
KV
KV
(EQ 5-10)
(EQ 5-11)
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I.V. Infusion
0.05 Q2
ln ------------------------Q1 Q2
T = ------------------------------------K
(EQ 5-12)
Combining equation 5-11 and equation 5-12 and rearranging results in:
Q1 Q2- 20 ln ----------------------Q1 Q2- 20
ln ----------------------
Q2
Q2
T = ---------------------------------------------- = ---------------------------------------------- t 1 2
K
0.693
(EQ 5-13)
Thus it is the absolute value of the difference of the two rates and the elimination
rate constant which determine the length of time needed to establish a new equilibrium. Under the conditions of Q1 = 0 , that is no previous infusion, and the difference is maximal equation 5-13 simplifies to equation 5-7. Under the conditions
of Q1 = Q2 , the equation is undifined and has no utility (as well as makes no
sense, because the equation was designed to be used when there was a change in
rate.) However, lim T = 0 , thus no change results in zero time to get to the new
Q2 Q1
equilibium. Similar to equation 5-7 as before, the generalization for the number of
half-lives it takes to obtain the new steady-state is the logarithm of (the fractional
difference of the rates (or the steady-state concentrations) times the inverse of how
close is close) devided by the logarithm of two.
As pharmacokinetic equations are additive, you should be able to determine a
loading dose (by I.V. bolus, for example) and a maintenance dose (infusion rate)
for a patient to extablish an equilibrium. If, for example, you want to give a loading dose followed by an IV infusion, the generalization for the number of halflives it takes to obtain the new steady-state is the logarithm of (the fractional difference of the concentrations, Cp0 and Cpss, times the inverse of how close is
close) devided by the logarithm of two.
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I.V. Infusion
Discussion:
Example: Using
population average
pharmacokinetic
parameters to make
professional judgements.
IV infusion is a controlled way to get drug into your patient. Using patient population average pharmacokinetic parameters (K, Vd) available in the drug monographs, you are able to make a professional judgement about:
1.
the plasma concentration that you would like to achieve (from therapeutic range) and the time in
which you would like to get there.
2.
3.
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I.V. Infusion
After setting up the infusion, the doctor asks, How long to steady state?
Using equation 5-7, our patient who has an eight hour half life, will take about
4.32 8 hr = 34.6 hr to get to 95% of steady state. The patient doesnt want
relief in a day and a half. He needs to breathe NOW. What would you suggest?
It might be possible to give him an IV Bolus dose stat which would get him to
Dose( C p )ss right away. This is done by converting
( C p )ss = -----------to
Vd
V d ( C p ) ss = Dose .
L- ------------kg - 200 lb 15 mg
0.45 ----------- = 613.6 mg Theophylline
kg 2.2 lb
L
Converting to aminophylline yields:
mg aminophylline 725 mg aminophylline . Thus,
613.6 mg Theophylline 100
-----------------------------------------------------85 mg theophylline
if we gave a 725 mg IV bolus dose of aminophylline followed by a concomitant
IV infusion of 500 mg aminophylline over 8 hours, our patient should get to
steady state right away and stay there.
Sometimes the physician might want to just increase the infusion rate (say double
it for a short time, 2Q) to get to the target concentration faster and then just back
the infusion down. If that is the protocol, the question becomes, How long do
you run the infusion in at the faster rate? Thus:
Kt
Kt
Q
2Q
( C p )ss = -------------- = -------------- ( 1 e ) which yields 1 = 2 ( 1 e ) and so
K Vd
K Vd
Kt
Kt
1
1
--- = 1 e
. Thus --- 1 = e . Taking the ln of both sides ln ( 0.5 ) = Kt
2
2
ln
( 0.5 ) = 0.693
------------------------------ t 1--- = t 1--- = t or that it will take one half-life to get to the target
K
0.693 2
2
plasma concentration (which is the Cpss obtained by the infusion rate of 1Q) if you
run the infusion at a faster rate, 2Q. So for your patient, you might suggest an
infusion of 1000 mg over 8 hours (2Q for one half life) to get to steady state
quickly and then back off to 500 mg over 8 hours for the second 8 hours.
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I.V. Infusion
Clearance: New
pharmacokinetic
parameter
How do we calculate
Clearance from IV infusion data?
(EQ 5-14)
(EQ 5-15)
Thus, assuming steady state, the clearance can be calculated by dividing the infusion rate by the resultant steady state plasma concentration.
How do we separate K
and Vd out of Clearance?
Graphing equation 5-4 which relates the decline in plasma concentration after cessation of the infusion, the resultant slope of the line yields - K, the elimination rate
constant. Dividing the elimination rate constant, - K, obtained by equation 5-4 into
the clearance obtained by equation 5-15 results in the other necessary pharmacokinetic parameter, Vd.
(EQ 5-16)
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I.V. Infusion
dCp
Q- K C and rearranging and incorporating equation 5-1 yields
= ----p
dt
Vd
dCp
Q- K -------------Q ( 1 e Kt ) which can be simplified to
= ----
dt
Vd
K Vd
dCp
Q- ----Q- + ----Q- e Kt or
= ----dt
V d V d Vd
dC p
Q- e Kt
= ----dt
Vd
(EQ 5-17)
dCp
Cp
vs. t ( actually,
----------- vs. tmid exactly like we did in urinary
dt
t
rate graphs) of the ascending portion of the plasma profile would result in a
Q- .
straight line with a slope of -K and an intercept of ----Vd
Thus a plot of
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I.V. Infusion
5.2 Problems
Equations needed for solving the problems:
1.
2.
0.693
t 1 2 = -----------k
3.
4.
Clearance Cl = K V d
5.
Q
K Vd
a.
Kt
b.
Dose loading = Cp ss V d
c.
T 95 = 4.32 T 1 2
d.
Find the plasma concentration if the infusion is discontinued at time = Tdc hours.
Q ( 1 e ( K Tdc ) ) .
Cp dc = -------------K Vd
e.
Find the plasma concentration Tpost hours after infusion is discontinued at time = Tdc hours.
Cp post = Cp dc e
( K T post )
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I.V. Infusion
Acyclovir
(Problem 5 - 1)
Laskin, O., "Clinical pharmacokinetics of acyclovir", Clinical Pharmacokinetics (1983), p. 187 - 201.
Acyclovir (225.21 g/Mole) is an antiviral drug used in the treatment of herpes simplex, varicella zoster, and in suppressive therapy. In this study, patients were given varying doses of acyclovir over one hour by infusion. Acyclovir distributes uniformly into the plasma and tissues such that the plasma concentration is representative of tissue concentration.
Acyclovir is 30% metabolized and 70% renally excreted. The following data was obtained from an intravenous infusion dose of 2.5 mg/kg over one hour where the patient weighed 70 kg.
PROBLEM TABLE 5 - 1. Acyclovir
Plasma concentration
Time (hours)
0
0.25
0.5
12
0.75
17
20
10
umol
-
-----------L
2.
t1 2
3.
Volume of distribution
4.
Clearance
5.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
e.
Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours.
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I.V. Infusion
Acyclovir on page 11
Concentration
102
101
100
0
Time
1.
2.
3.
4.
5.
Calculate the infusion rate necessary to maintain a plasma concentration of 25 umol L = 111 mg/hr
b.
Suggest a loading dose for the patient which would give you Cpss immediately. 148 mg
c.
d.
Find the plasma concentration if the infusion is discontinued at time = 5 hours. = 25 umol L
e.
Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours. = 5.6 umol L
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I.V. Infusion
Aminophylline
(Problem 5 - 2)
Gilman, T., et al., "Estimation of theophylline clearance during intravenous aminophylline infusions", Journal of Pharmaceutical
Sciences (May 1985), p. 508 - 514.
Aminophylline is used in the treatment of bronchospasm. In this study, aminophylline was given by intravenous infusion to patients with a mean weight of 75.7 kg. The doses given were chosen to maintain a between 10 -20 mg/L based
on desirable body weight. The doses were given at a rate of 0.5 mg/kg/hour (Theophylline) for 84 hr. The following
set of data was collected.
PROBLEM TABLE 5 - 2. Aminophylline
Plasma concentration
Time (hours)
0
mg
------L
0.
12
24
11
30
11.6
36
12.0
48
12.4
54
12.5
66
12.6
72
12.8
84
12.8
88
92
6.4
96
4.6
100
3.2
2.
t1 2
3.
Volume of distribution
4.
Clearance
5.
6.
a.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
e.
Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours.
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I.V. Infusion
Aminophylline on page 13
CONCENTRATION
102
101
10
20
40
60
80
100
Time
1.
k = 0.085 hr-1
2.
t 1 2 = 8.15 hr
3.
Vd = 35.3 L
4.
Cl = 3 L/hr
5a.
Q = 45 mg/hr
5b.
D L = 530 mg
5c.
5d.
C p = 5.2 mg/L
5e.
C p = 4.4 mg/L
ss
= 35 hr
95%
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I.V. Infusion
Carmustine
(Problem 5 - 3)
Henner, W., et al., "Pharmacokinetics and immediate effects of high-dose carmustine in man", Cancer Treatment Reports vol.70
(1986), p. 877 - 880.
In this study a 70 kg, 1.8 M2 patient was given 600 mg m by intravenous infusion over 2 hours. The following data
was obtained.
PROBLEM TABLE 5 - 3. Carmustine
Plasma concentration
Time (minutes)
15
.3
30
.5
60
.7
90
.75
120
.8
135
.5
142.5
.4
150
.3
mg
------L
2.
t1 2
3.
Vd
Cl
5.
A patient with a BSA of1.8 M is to be given BCNU by IV infusion. You wish to maintain a plasma
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
e.
Find the plasma concentration 1 hour after infusion is discontinued at time = 10 minutes.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-15
I.V. Infusion
Carmustine on page 15
CONCENTRATION
10
-1
10
50
100
150
TIME
1.
k = 0.031 min-1
2.
t 1 2 = 22 min
3.
Vd = 198 L/M2
Cl = 6.15 L/M2/hr
5.
A patient with a BSA of1.8 M is to be given BCNU by IV infusion. You wish to maintain a plasma
Suggest
loading
dose
for
the
patient
which
would
give
you
Cpss
immediately.
How long will it take to reach steady state? 4.32 * T 1/2 = 97 min.
d.
Find the plasma concentration if the infusion is discontinued at time = 10 min. = 0.1197 mg/L
e.
Find the plasma concentration 1 hour after infusion is discontinued at time = 10 min. = 0.017 mg/L
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-16
I.V. Infusion
Cefotaxime
(Problem 5 - 4)
Kearns, G., Young, R., and Jacobs, R., "Cefotaxime dosage in infants and children--pharmacokinetic and clinical rationale for an
extended dosage interval", Clinical Pharmacokinetics (1992), p. 284 - 297.
Cefotaxime is a third generation cephalosporin which is widely used as an antimicrobial in neonates, infants, and children. In this study, infants and children were given a 50 mg/kg dose of cefotaxime intravenously over 0.25 hour. The
following data was collected:
PROBLEM TABLE 5 - 4. Cefotaxime
Plasma concentration
Time (hours)
0.00
0.05
35
0.10
70
0.20
140
0.35
155
0.60
130
0.85
110
1.20
80
1.30
75
2.00
45
2.40
35
3.40
15
4.50
6.50
1.7
mg
------L
From this data, assuming that the patient weighs 30 kg, determine the following:
1.
2.
t1 2
3.
Vd
4.
Cl
5.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
Find the plasma concentration if the infusion is discontinued at time = 0.25 hours.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-17
I.V. Infusion
e.
Find the plasma concentration 2 hours after infusion is discontinued at time = 0.25 hours.
Cefotaxime on page 17
CONCENTRATION
103
102
101
100
0
TIME
1.
k = 0.733 hr-1
2.
t 1 2 = 0.945 hr
3.
Vd = 0.276 L/kg
4.
Cl = 0.202 L/kg/hr
4a.
Q = 16.2 mg/kg/hr
4b.
D L = 22.1 mg/kg
4c.
4d.
C p = 13.35 mg/L
4e.
C p = 3.09 mg/L
ss
= 4.1 hr
95%
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-18
I.V. Infusion
Ganciclovir
(Problem 5 - 5)
Trang, J., et al., "Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections",
Clinical Pharmacology and Therapeutics (1993), p. 15 - 21.
Ganciclovir is used against the human herpes viruses, cytomegalovirus retinitis, and cytomegalovirus infections of the
gastrointestinal tract. In this study, twenty-seven newborns with cytomegalovirus disease were given 4 mg/kg of ganciclovir intravenously over one hour. Blood samples were taken and the data obtained is summarized in the following
table:
PROBLEM TABLE 5 - 5. Ganciclovir
ug
mL
Time (hours)
0.5
3.10
1.5
4.50
2.0
3.80
3.0
2.90
4.0
2.30
6.0
1.50
8.0
0.88
2.
t1 2
3.
Vd
4.
Cl
4.
A patient is to be given ganciclovir by IV infusion to an infant weighing 6.1 kg. You wish
to maintain a plasma concentration of 5.5 mcg/mL. Determine the following:
a.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
e.
Find the plasma concentration 2 hours after infusion is discontinued at time = 1 hour.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-19
I.V. Infusion
Ganciclovir on page 19
CONCENTRATION
10 1
10 0
10-1
0
Time
1.
k = 0.255 hr-1
2.
t 1 2 = 2.72 hr
3.
Vd = 0.687 L/kg
4.
Cl = 0.175 L/kg/hr
5a.
mg - -----------------1000ml 0.687L
Q = Cp ss V d K = 5.5g
-------------- ------------------ 6.1kg 0.255
------------- = 5.9mg
-------------- ---------------ml 1000g
L
kg
hr
hr
5b.
mg - -----------------1000ml 0.687L
D L = Cp ss Vd = 5.5g
-------------- ---------------------------------- 6.1kg = 23mg
kg
ml 1000g
L
5c.
ss
= 4.32 t1 2 = 11.75hr
95%
5.9mg
-------------- Kt
K 1hr
Q
hr
= -------------- ( 1 e ) = ----------------------------------------------------- (1 e
) = 1.24mg
-----------------K Vd
0.255
L
------------- 0.687L
----------------- 6.1kg
hr
kg
5d.
C p term
5e.
C p = C p term e
K 2hr
= 1.24mg
------------------ 0.6 = 0.74mg
-----------------L
L
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-20
I.V. Infusion
Gentamicin
(Problem 5 - 6)
AHFS 00:00.00
Kaojarern, S., et al., "Dosing regimen of gentamicin during intermittent peritoneal dialysis", Journal of Clinical Pharmacology
(1989), p. 140 - 143.
Gentamicin is an aminoglycoside antibiotic which is frequently used in the treatment of gram-negative bacilli infections. Since it has a low therapeutic index, it is important to determine proper dosage regimens. In this study, patients
on peritoneal dialysis received a 30 minute intravenous infusion of 80 mg gentamicin in 100 mL of 5% dextrose in
water. The following data was collected:
PROBLEM TABLE 5 - 6. Gentamicin
Plasma concentration
Time (hours)
0.50
5.68
1.50
5.15
3.70
4.80
7.35
3.99
11.30
3.35
24.00
2.02
ug
------ mL-
2.
t1 2
3.
Vd
4.
Cl
5.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
Find the plasma concentration if the infusion is discontinued at time = 0.5 hours.
e.
Find the plasma concentration 2 hours after infusion is discontinued at time = 0.5 hours.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-21
I.V. Infusion
Gentamicin on page 21
CONCENTRATION
101
100
0
10
15
20
25
Time
1.
k = 0.0431 hr-1
2.
t 1 2 = 16.1 hr
3.
V d = 14.5 L
4.
Cl =0.625 L/hr
5a.
Q = 3.25 mg/hr
5b.
D L = 75 mg
5c.
5d.
C p = 0.11 mg/L
5e.
C p = 0.10 mg/L
ss
= 69.6 hr
95%
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-22
I.V. Infusion
(Problem 5 - 7)
Fisher, C., et al., "Initial evaluation of human monoclonal anti-lipid A antibody (HA-1A) in patients with sepsis syndrome", Critical Care Medicine (1990), Vol.18, No. 12, p. 1311 - 1315.
HA-1A is an immunoglobulin antibody. In this study, patients received a 250 mg intravenous infusion of HA-1A over
15 minutes. Serum levels were measured before and after infusion and the following data was collected:
PROBLEM TABLE 5 - 7. Human
Plasma concentration
Time (hours)
0.00
0.75
80
1.00
75
2.00
74
5.00
65
15.00
50
25.00
40
48.00
21
72.00
10
ug-
------ mL
2.
t1 2
3.
Vd
4.
Cl
100 g/mL.
a.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
e.
Find the plasma concentration 3 hours after infusion is discontinued at time = 1 hour.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-23
I.V. Infusion
CONCENTRATION
102
101
0
20
40
60
80
Time
1.
k = 0.0282 hr-1
2.
t 1 2 = 24.4 hr
3.
V d = 3.2 L
4.
Cl = 0.09 L/hr
5a.
Q = 9 mg/hr
5b.
D L = 320 mg
5c.
5d.
C p = 2.78 mg/L
5e.
C p = 2.56 mg/L
ss
= 105 hr
95%
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-24
I.V. Infusion
Ifosfamide
(Problem 5 - 8)
AHFS 00:00.00
GPI: 0000000000
Lewis, L., "The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients", British Journal
of Clinical Pharmacology Vol. 31 (1991), p. 77 - 82.
Ifosfamide is an agent which has shown some pharmacological response in the treatment of cancer. In this study, a 5
gm
dose of ifosfamide was infused over 30 minutes. The median BSA for the subjects was 1.8 m . The
Plasma concentration
Time (hours)
0
0.0
0.5
285.0
260.0
220.0
160.0
112.0
80.0
10
60.0
24
ug
------ mL-
2.
t1 2
3.
Vd
4.
Cl
5.
A patient is to be given ifosfamide by IV infusion. The patient has a BSA 1.8 M2. You wish to maintain a
plasma concentration of 336 g/mL. Determine the following:
a.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
e.
Find the plasma concentration 2 hours after infusion is discontinued at time = 20min.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-25
I.V. Infusion
Ifosfamide on page 25
CONCENTRATION
103
102
101
100
0
10
15
20
25
Time
1.
k = 0.1716 hr-1
2.
t 1 2 = 4.04 hr
3.
V d = 16.6 L/M2
4.
Cl = 2.85 L/hr/M2
5a.
Q = 1.725 g/hr
5b.
D L = 10 g
5c.
5d.
C p = 18.7 mg/L
5e.
C p = 13.25 mg/L
ss
= 17.5
95%
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-26
I.V. Infusion
Isosorbide 5-mononitrate
Problem Submitted By: Maya Leicht
AHFS 00:00.00
GPI: 0000000000
(Problem 5 - 9)
Isosorbide 5-mononitrate (5-ISMN) is a metabolite of isosorbide dinitrate. In this study, the kinetics of isosorbide 5mononitrate were looked at in 12 healthy patients after an intravenous infusion of 20 mg at 8 mg/hour for 2.5 hours.
This drug follows one-compartment, open model kinetics. The following data was collected:
PROBLEM TABLE 5 - 9. Isosorbide
5-mononitrate
Time (hours)
0.25
40
0.50
91
0.75
141
1.00
181
1.50
239
2.00
305
2.50
351
3.00
335
3.50
303
4.50
257
5.50
216
7.50
162
9.50
117
11.50
77
14.50
47
18.50
24
26.50
2.
t1 2
3.
Vd
4.
Cl
5.
Calculate the infusion rate necessary to maintain a plasma concentration of 300 ng/mL.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
e.
Find the plasma concentration 2 hours after infusion is discontinued at time = 1 hour.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-27
I.V. Infusion
CONCENTRATION
103
102
101
100
0
10
15
20
25
30
Time
1.
k = 0.168 hr-1
2.
t 1 2 = 4.125 hr
3.
V d = 44.6 L
4.
Cl = 7.5 L/hr
5a.
Q = 2.25 mg/hr
5b.
D L = 13.4 mg
5c.
5d.
C p = 46.4 ng/mL
5e.
C p = 33.2 ng/mL
ss
= 17.8 hr
95%
Basic Pharmacokinetics
REV. 99.4.25
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5-28
I.V. Infusion
Moclobemide
(Problem 5 - 10)
AHFS 00:00.00
GPI: 0000000000
Schoerlin, M., et al., "Disposition kinetics of moclobemide a new MAO-A inhibitor, in subjects with impaired renal function", Journal of Clinical Pharmacology Vol 30 (1990), p. 272 - 284.
Moclobemide is reversibly inhibits the A-isozyme of the monoamine oxidase enzyme system. In this study, twelve
patients received a 96.7 mg dose as an intravenous infusion over 20 minutes. Blood samples were obtained during the
infusion and after the infusion was ended and the following data was obtained:
PROBLEM TABLE 5 - 10. Moclobemide
Time (hours)
0.0
0.000
0.2
0.6
0.4
0.7
0.85
0.9
0.750
1.2
0.70
1.6
0.60
1.9
0.50
2.4
0.40
3.4
0.25
4.5
0.15
5.5
0.10
6.4
0.070
2.
t1 2
3.
Vd
4.
Cl
5.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
Basic Pharmacokinetics
REV. 99.4.25
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5-29
I.V. Infusion
e.
Find the plasma concentration 3 hours after infusion is discontinued at time = 15 mins.
Moclobemide on page 29
CONCENTRATION
10 0
10-1
10-2
0
1.
k = 0.44 hr-1
2.
t 1 2 = 1.6 hr.
3.
V d = 90.4 L
4.
Cl = 39.8 L/hr
5a.
Q = 40 mg/hr
5b.
D L = 90 mg
5c.
5d.
C p = 0.1 mg/L
5e.
C p = 0.028 mg/L
Time
ss
= 6.8 hr
95%
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-30
I.V. Infusion
Obidoxime
(Problem 5 - 11)
AHFS 00:00.00
GPI: 0000000000
Bentur, Y., et al., "Pharmacokinetics of obidoxime in organophosphate poisoning associated with renal failure", Clinical Toxicology (1993), Vol. 31, p. 315 - 322.
Obidoxime is an agent which is used as an antidote in organophosphate poisoning. In this study, the pharmacokinetics
of obidoxime were studied in a 20 year old patient who attempted to commit suicide by ingesting Tamaron (60% methamidophos, an organophosphate, in ethylene glycol monethyl ether). She was given 4 mg/kg Obidoxime by intravenous infusion over 10 minutes and the following data was collected:
PROBLEM TABLE 5 - 11. Obidoxime
Time (minutes)
Plasma concentration
10
18
15
17
30
16
45
15
60
14
90
12
120
11
150
9.3
180
240
6.1
300
4.6
g mL
2.
t1 2
3.
Vd
4.
Cl
5.
A patient is to be given obidoxime by IV infusion. The patient has a body weight of 60 kg.
You wish to maintain a plasma concentration of 10 g/mL. Determine the following:
a.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
Basic Pharmacokinetics
REV. 99.4.25
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5-31
I.V. Infusion
e.
Find the plasma concentration 1 hour after infusion is discontinued at time = 30 minutes.
Obidoxime on page 31
CONCENTRATION
102
101
100
0
50
100
150
200
250
300
Time
1.
k = 0.00463 min-1
2.
t 1 2 = 150 min
3.
V d = 0.22L/kg
4.
Cl = 1 mL/min
5a.
Q = 0.61 mg/min
5b.
D L = 132 mg
5c.
5d.
C p = 1.3 mg/L
5e.
C p = 0.98 mg/L
ss
= 10.8 hr
95%
Basic Pharmacokinetics
REV. 99.4.25
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5-32
I.V. Infusion
Perindoprilat
(Problem 5 - 12)
AHFS 00:00.00
GPI: 0000000000
Macfadyen, R., Lees, K., and Reid, J., "Studies with low dose intravenous diacid ACE inhibitor (perindoprilat) infusions in normotensive male volunteers", Journal of Pharmaceutical Sciences (1991), p. 115 - 121.
Perindoprilat and other ACE inhibitors are used in the management of hypertension and chronic congestive heart failure. In this study, a 1 mg dose was infused over a one hour period. The following data was collected:
PROBLEM TABLE 5 - 12. Perindoprilat
Time (minutes)
Plasma concentration
4.0
10
9.0
20
16.0
30
24.0
40
30.0
50
36.0
60
42.0
65
40.0
70
38.0
80
35.0
90
32.0
100
29.0
110
27.0
120
24.0
ng mL
2.
t1 2
3.
Vd
4.
Cl
5.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
Basic Pharmacokinetics
REV. 99.4.25
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5-33
I.V. Infusion
e.
Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours.
Perindoprilat on page 33
CONCENTRATION
102
101
100
0
20
40
60
80
100
120
Time
1.
k = 0.0087 min-1
2.
t 1 2 = 79.6 min
3.
V d = 18.9 L
4.
Cl =164 mL/min
5a.
Q = 5 g/min
5b.
D L = 0.57 mg
5c.
5d.
C p = 27.8 ng/mL
5e.
C p = 9.8 ng/mL
ss
= 5.73 hr
95%
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-34
I.V. Infusion
Sulfonamides
(Problem 5 - 13)
AHFS 00:00.00
GPI: 0000000000
Boddy, A., Edwards, P., and Rowland, M., "Binding of sulfonamides to carbonic anhydrase: influence on distribution within blood
and on pharmacokinetics", Pharmaceutical Research (1989), p. 203- 209
This study looks at the affinity of sulfonamides for carbonic anhydrase. Doses of 8 micromoles/kg were administered
via the jugular vein cannula in approximately 0.5 mL of PEG 400 over 5 minutes at a constant rate. Samples were collected during the infusion period and for 30 minutes afterward. The following set of data was collected:
PROBLEM TABLE 5 - 13.
Sulfonamides
Time (minutes)
Plasma concentration
2.0
17.0
4.0
31.0
5.0
37.0
7.5
32.0
9.0
28.0
12.0
22.5
15.0
18.0
18.0
14.0
23.0
11.0
30.0
6.5
35.0
4.5
( M )
2.
t1 2
3.
Vd
4.
Cl
5.
Calculate the infusion rate which would be necessary to maintain the plasma concentration of 30 M.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
Basic Pharmacokinetics
REV. 99.4.25
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5-35
I.V. Infusion
e.
Find the plasma concentration 30 minutes after stopping infusion at time = 4 hours.
Sulfonamides on page 35
CONCENTRATION
102
101
100
0
10
15
20
25
30
35
Time
1.
k = 0.0705 min-1
2.
t 1 2 = 9.8 min
3.
V d = 0.18 L/kg
4.
Cl = 12.7 mL/min/kg
5a.
Q = 26.9 mole/min
5b.
D L = 380 mole
5c.
5d.
C p = 30 mole/L
5e.
C p = 3.6 mole/L
ss
= 42 min
95%
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-36
I.V. Infusion
Terodiline
(Problem 5 - 14)
AHFS 00:00.00
GPI: 0000000000
Hallen, B. ,et al., "Bioavailability and disposition of terodiline in man", Journal of Pharmaceutical Sciences (1994), p. 1241 1246.
Terodiline is an agent which works as an anticholinergic and a calcium antagonist. It is used to treat incontinence. It
is metabolized into p-Hydroxyterodiline, which is further metabolized to 3,4-dihydroxyterodiline. The parent drug and
all of its metabolites are excreted into the urine as well as the feces. A patient is given 12.5 mg of Terodiline by IV
infusion at a rate of 1 mL/ minute for 5 minutes. The following data is collected:
PROBLEM TABLE 5 - 14.
Terodiline
Time (hours)
Plasma concentration
25.000
31
50.000
23
75.000
15
100.000
12
125.000
150.000
175.000
200.000
225.000
g L
2.
t1 2
3.
Vd
4.
Cl
5.
Calculate the infusion rate necessary to maintain the plasma concentration of40 mcg/L.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
e.
Find the plasma concentration 2 hours after stopping infusion if the infusion ended at
time = 5 hours.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-37
I.V. Infusion
Terodiline on page 37
CONCENTRATION
102
101
100
0
50
100
150
200
250
Time
1.
k = 0.0136 hr-1
2.
t 1 2 = 50.9 hr
3.
V d = 283 L
4.
Cl =3.85 L/hr
5a.
Q = 0.154 mg / hr
5b.
D L = 11.32 mg
5c.
5d.
C p = 2.63 g/L
5e.
C p = 2.56 g/L
ss
= 220 hr
95%
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-38
I.V. Infusion
Tinidazole
(Problem 5 - 15)
AHFS 00:00.00
GPI: 0000000000
Robson, R., Bailey, R., and Sharman, J., "Tinidazole pharmacokinetics in severe renal failure", Clinical Pharmacokinetics (1984),
p. 88 - 94.
Tinidazole is an antimicrobial similar to metronidazole which is used in the treatment of trichomoniasis, giardiasis,
amoebiasis, and anaerobic infections. This study focuses on the pharmacokinetics of tinidazole in patients suffering
from severe renal failure. Twelve patients received 800 mg of tinidazole dissolved in 400 mL of dextrose monohydrate
solution as an intravenous infusion at a rate of 60 mg/min. Blood samples were taken and the following data was
obtained:
PROBLEM TABLE 5 - 15.
Tinidazole
Time (hours)
14.9
13.1
11.2
12
8.9
24
5.1
48
2.1
2.
t1 2
3.
Vd
4.
Cl
5.
Calculate the infusion rate necessary to maintain the plasma concentration of 25 mg/L.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
e.
Find the plasma concentration 2 hours after stopping infusion if the infusion was stopped
at time = 1 hour.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
5-39
I.V. Infusion
Tinidazole on page 39
CONCENTRATION
102
101
100
0
10
1.
k = 0.04136 hr-1
2.
t 1 2 = 16.75 hr
3.
V d = 54.7 L
4.
Cl = 2.26 L/hr
5a.
Q = 56.6 mg/hr
5b.
D L = 1.37 g
5c.
5d.
C p = 1 mg/L
5e.
C p = 0.93 mg/L
20
Time
30
40
50
ss
= 72.4 hr
95%
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5-40
I.V. Infusion
Tobramycin
(Problem 5 - 16)
AHFS 00:00.00
GPI: 0000000000
Cooney, G., et al., "Absolute bioavailability and absorption characteristics of aerosolized tobramycin in adults with cystic fibrosis", Journal of Clinical Pharmacology Vol. 34, (1994), p. 255- 259.
Most persons with cystic fibrosis (CF) become colonized with Pseudomonas aeruginosa in their bronchial secretions
within their second decade of life. These patients require frequent treatment with potent anti-pseudomonal antibiotics
such as Tobramycin. In this study, an intravenous infusion of 2.5 mg/kg tobramycin was given over 35 minutes. The
following data was collected:
PROBLEM TABLE 5 - 16.
Tobramycin
Plasma concentration
Time (minutes)
35
8.00
60
6.00
90
4.50
150
2.50
270
0.75
mg
------L
2.
t1 2
3.
Vd
4.
Cl
5.
A patient is to be given tobramycin by IV infusion. The patient has a body weight of 70 kg. You wish
to maintain a plasma concentration of 10 mg/L. Determine the following:
a.
Calculate the infusion rate necessary to maintain the plasma concentration of 10 mg/mL.
b.
Suggest a loading dose for the patient which would give you Cpss immediately.
c.
d.
e.
Find the plasma concentration 1 hour after stopping infusion if the infusion wasstopped at
time = 30 minutes.
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5-41
I.V. Infusion
Tobramycin on page 41
CONCENTRATION
101
100
10-1
0
50
100
150
200
250
300
Time
1.
k = 0.01 min-1
2.
t 1 2 = 69.3 min
3.
V d = 0.269 L/kg
4.
Cl = 2.7 mL/min
5a.
5b.
D L = 2.7 mg/kg
5c.
5d.
C p = 2.6 mg/L
5e.
C p = 1.43 mg/L
ss
= 300 min = 5 hr
95%
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5-42
CHAPTER 6
Biopharmaceutical Factors
OBJECTIVES
After successfully completing this chapter, the student shall understand:
1.
2.
3.
4.
5.
identify the effects of physiological changes with age, sex, and disease on the
absorption, distribution, metabolism, and excretion of a drug.
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CHAPTER 7
Oral Dosing
OBJECTIVES
After successfully completing this chapter, the student shall be able to
1.
Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the relevant pharmacokinetic parameters ( V d , K, k m , k r , k a , AUC ,
Clearance, MRT, MAT) available from oral data.
2.
Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the K from the terminal portion of the curve.
3.
Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the k a from either the curve stripping Moment techniques.
4.
Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the Absolute Bioavailability from comparing IV and oral (or
some other process which involves absorption) data.
5.
Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the Comparative Bioavailability from comparing the generic to the
inovator product.
6.
Given patient drug concentration and/or amount vs. Time profiles, the student will
qualitatively evaluate (IV) bioequivalence as determined by rate of absorption
(peak time) and extent of absorption (Area Under the Curve - AUC, and ( Cp ) max ).
7.
Given patient drug concentration and/or amount vs. Time profiles, the student will
evaluate (IV) bioequivalence data.
8.
Given patient drug concentration and/or amount vs. Time profiles, the student will
lucidly discuss (IV) bioequivalence and recommend (V) to another competant
professional if s/he believes products to be equivalent.
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Oral Dosing
9.
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7-2
Oral Dosing
where
CB
ka
k t
Kt
C p = fD
------ -------------- (e e a )
Vd k a K
(EQ 5-18)
(EQ 5-19)
(EQ 5-20)
ln ( k a K )
t p = ----------------------( ka K )
(EQ 5-21)
X
-----a- = K AUC ( C p + K AUC t )
v
(EQ 5-22)
f = the absolute bioavailabilty; the fraction of dose which ultimately reaches systemic circulation (which is made up of the fraction of the dose which is absorbed
times the fraction which gets past the liver (first pass effect))
ka
7.1.2
UTILIZATION
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Oral Dosing
Ampicillin
(Problem 5 - 17)
The following information is available for ampicillin: 90% is excreted unchanged and a 250 mg IV bolus dose yields an
AUC of 11 mic/mL*hr. The following blood level profile has been reported for two brands of ampicillin which were
given as 500 mg oral capsules.
TABLE 4-7
Time (hr)
g
MEAN SERUM LEVEL -------mL
LEDERLE
BRISTOL
0.5
0.37
0.38
1.0
1.97
1.91
1.5
2.83
2.49
2.0
3.15
3.11
3.0
2.73
2.79
4.0
1.86
1.95
6.0
0.43
0.49
b.
c.
d.
e.
f.
g.
Cl
h.
Vd
j.
Cp max
k.
l.
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Oral Dosing
The data was plotted as above with the best fit line drawn. From the graph the following parameters were derived:
TABLE 4-8 Comparison
of Ampicillin
Lederle
Bristol
K ( hr )
0.688
0.635
Ratio (L/B)
K a ( hr )
0.858
0.831
T max ( hr )
1.74
1.8
0.97
( C p ) max ( g mL )
2.9
1.03
AUC (trapaziodal)
11.4
11.6
0.98
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Oral Dosing
0.5
40.8
57.3
70.0
77.1
79.5
82.3
80.7
69.4
68.6
60.6
49.4
48.0
35.0
33.7
12
15.3
17.4
24
2.1
3.0
Answer:
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Oral Dosing
Product A
Ka (hr^-1)
1.19
Tmax (hr)
Product B
Ratio (A/B)
1.8
2
1.52
1.31
Cmax (mcg/100mL)83.2
82.8
1.00
AUC (trapazoidal)676.52
688.81
0.976
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Oral Dosing
5.2
5.4
Duration (hr)
4.5
0.34
0.65
4.0
4.2
4.4
1.0
2.0
time(hrs)
(ug/ml)
time(hrs)
(ug/ml)
1.79
0.45
1.36
12
0.08
0.78
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7-8
Oral Dosing
IV Bolus Parameters:
Cp max2.4 mic/mL
AUC 8.5
K
0.283 hr^-1
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Oral Dosing
f} How long would it take that infusion to attain a therapeutic plasma concentration of 0.5 mic/ml ?
Cp = Q/(K*V)(1-exp(-K*T) = 0.5 = 26.54/(0.283*125)*(1-exp(-0.283*T)) --> 3.9
hr
4) LYSERGIC ACID DIETHYLAMIDE (LSD) was given to human volunteers at
the dose of 150 mic orally. (Impregnated blotter dosage form.) The following data
was obtained:
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7-10
Oral Dosing
Time
Cp (ng/ml)
Time
2.0
Cp (ng/ml)
0.25
1.75
4.6
0.5
2.9
3.0
4.1
0.75
3.7
4.0
3.3
1.0
4.2
6.0
2.1
1.5
4.6
8.0
1.4
a) Find ka
% Control
Cp (ng/ml)
5.5
33
1.5
65
4.1
40
1.1
80
2.9
52
% Control
If 100 mic dose were given by IV bolus, how long would it be before the volunteer
would regain 80% of his control?
Answwer:
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Oral Dosing
Cpmax
4.63 ng/mL
T max
1.7 hr
AUC (trap)30.07
K
0.225 hr^-1
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Oral Dosing
m (-K)
-0.225 hr^-1
Ka
1.22 hr^-1
f (AUCoral/Doseoral)/(AUCiv/Doseiv) = .98
100 mic dose IV yields Cp0 of (Cp0 =AUC * K = 20.4 * 0.225) 4.59ng/mL.
= 6.76 hours
5. The following data was collected from a double blind cross over study between
500 mg dose of cloxacillin made by Bristol (Tegopen@) and a generic product
which you might want to put in your store.
Time
(Conc. mic/ml)
Time
TEGOPEN GENERIC
(Conc. mic/ml)
TEGOPEN GENERIC
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Oral Dosing
0.25
.41
0.1
1.5
6.93
7.75
0.5
8.56
6.39
4.95
5.16
0.75
11.97
11.44
11.28
11.42
9.57
9.64
1.25
3
4
2.19
1.48
2.29
1.30
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Oral Dosing
Cpmax (mic/mL)10.8
GenericRatio (G/T)
9.94
0.92
T max (hr)
0.74
0.89
1.20
AUC (trap)
21.7
21.06
0.97
K (hr^-1)
0.72
0.8
ka (hr^-1)
4.3
2.69
Actual evaluation of ka and peak time is dificult because of the pucity of data at
early time points however all relavent parameters meet guidlines.
7. The F.D.A. reported the following data submitted to be consideration regarding
the equivalence of Mylan Pharmaceuticals' Tetracycline with that of Lederle and
an intervenous bolus dose. (Dose 250 mg).
Time(hrs) Conc.(mcg/ml) Time(hrs)
Lederle Mylan I.V.
Conc.(mcg/ml)
0.5
1.5
12
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Oral Dosing
15
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Oral Dosing
Pharmacokinetic parameters:
Lederle
Cpmax (mic/mL)2.75 2.42
Tmax (hr)
3.04
AUC
Mylan
IV
5.65
3.08
26.4
0
23.3
k (hr^-1)
0.165
0.161
Ka (hr^-1)
0.684
0.729
31.4
0.167
Ratio of bioequivalence parameters (Cpmax, Tmax and AUC) are all within guidelines. So, the would be considered bioequivalent.
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Oral Dosing
Dose the kid gets is mom's plasma concentration * Ratio(M/b) * volume of milk /
day = 3 mic/mL * 200 * 60cc * 12 feedings = 432 mg.day
Mom gets 1000 mg/day
Ratio of dose on a mg/kg basis (kid/mom) = (432/5)/1000/50) = 4.32 - Kid's getting more than mom.
Fifty miligrams of ketameperidine was given by IV bolus. The following urinary
profile was obtained for the only metabolite N-methyl-ketameperidine:
0.0 - 0.5
2.26
0.5 - 1.5
5.83
1.5 - 2.5
5.43
2.5 - 3.5
4.60
3.5 - 5.0
2.36
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Oral Dosing
5.0 - 7.0
1.47
7.0 -10.0
0.96
10.0 -18.0
0.44
Answer:
With only one data point in the early time points, the larger rate constant is in question. The terminal slope is assumed to be K. The AUC will yield the amount of
ketameperidine which was metabolized (dXmu/dt * t = Xmu).
K (hours^-1) 0.216
AUC (mg)30.3
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Oral Dosing
kr = K - km = 0.085 hours^-1
Aminophylline consists of THEOPHYLLINE (85% W/W) & Ethylene diamine
(15% W/W)
THEOPHYLLINE is the active compound measured in blood.
THEOPHYLLINE has a volume of distribution of 0.45 l/kg.
THEOPHYLLINE is 10% excreted unchanged and 90% metabolized to inactive
metabolites.
THEOPHYLLINE has a therapeutic range between 20 and 10 mg/l.
AUC FROM 0 to infinity for THEOPHYLLINE (given as 400 mg AMINPHYLLINE) is 120 mg/l x hr.
The average plasma concentration of THEOPHYLLINE given as 400 mg of AMINOPHYLLINE is as follows:
time
conc. time
conc.
(hrs)
(mg/L) (hrs)
(mg/L)
0.5
7.24
4.0
8.06
1.0
9.56
6.0
6.89
2.0
10.00 8.0
5.57
3.0
8.84
4.53
10.0
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Oral Dosing
Answer:
AUC (mg/L)*hr117.8
K (hr^-1)
0.096
ka (hr^-1)
2.11
f = (AUCoral/DOSEoral)/(AUCiv/DOSEiv) =
= (117.8 / 400 )/(120 / 400 ) = 0.98
Vd
AUC * K = Cp0iv
120 * 0.096 = 11.52 mg/L
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Oral Dosing
Infusion rate = Q = Cpss * TBC = 15 mg/L * 2.83 L/hr = 42.45 mg/hr Theophylline = 42.45/.85 = 50 mg/hr Aminophylline
Abbott labs has provided the following data conserning their ORETIC tablets
(hydrochlorthiazide tablets U.S.P.) Dose given was 50 mg.
time
conc. time
conc.
(hrs)
(mg/L) (hrs)
(mg/L)
0.5
0.05
3.0
0.31
1.0
0.21
4.5
0.23
1.5
0.27
6.0
0.18
2.0
0.31
8.0
0.12
Answer:
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Oral Dosing
The data is plotted both without (first figure) and with (second figure) a lag-time
which is associated with the release of the drug from the delivery system. Note
that the addition of the lag-time improves the fit.
WithoutWith
Cpmax (mg/L)0.22
0.31
Tmax (hr)
2.28
3.45
AUC (mg/L*hr)2.2
2.26
K (hr^-1)
0.216
0.201
ka (hr^-1)
0.380
1.10
t lag (hr)
0.0
0.393
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Oral Dosing
Wilkenstein et al.(Gastroenterology 74:360,1978) tested 12 normal healthy volunteers in a four way crossover design of four dosage forms containing 300 mg of
cimetadine. The following data was obtained:
A
B
C
D
AUC(mic/ml x hr)
---
---
5.2
54.9
55.8
Duration (hr)
4.5
1.53
1.44
4.6
5.4
0.34
0.65
4.2
4.4
1.0
2.0
conc.(ug/ml)
1.79
1.36
0.78
0.45
12
0.08
a} find K, Cp0.
Both can be found from the graph. K = .283/hr Cp0 = 2.36 mic/ml
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Oral Dosing
d} How can you explain the variation in % recovered intact in the urine?
g} How long would it take that infusion rate to attain a therapeutic plasma concentration of 0.5 mic/ml ?
Cp = Q/(K * V)(1-exp(-K*T) = 0.5 = 26.54/(0.283 *125)*(1-exp(-0.283 * T)) > 3.9 hr
Roxane labs of Columbus, Ohio offers the following data for your review of their
Quinidine Sulfate tablets (Dose 200 mg). It is compared against the reference
standard by Ely Lilly and company at the same dose.
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Oral Dosing
Lilly
.42
.58
.73
.77
.71
.74
.61
.66
.45
.52
.32
.34
12
.20
.22
Answers
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Oral Dosing
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Oral Dosing
w/o
Rw/o(R/L)Rw(R/L)
0.97
0.91
Tmax (hr)
2.69
2.05
2.33
2.10
T lag (hr)
0.0
0.70
0.0
0.36
1.15
0.98
Answers:
--
50
--
77
1.5
--
100
29
100
24
90
18
78
15
59
11
45
32
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Oral Dosing
a) find ka
b) Calculate the absolute bioavailability of propranolol.
c) Calculate TBC
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Oral Dosing
IV data
Oral Data
w/o
99.7
Tmax (hr)
2.0
K (hr^-1)
0.239
0.324 0.421
ka (hr^-1)
---
0.715 0.548
2.1
T lag
0.0
0.02
= 50 L/hr or
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Oral Dosing
a) Calculate TBC
TBC = K * V = (0.198/hr)(100L) = 19.8 L/hr
c) Calculate the effect on total body clearance in a patient with viral hepititis (FI =
0.3).
Clh*/Clh = (.3)(1)/1 + .6(.3 - 1) = .3/.58 = .517
(.517)(18.8) = 9.72
TBC = 1 + 9.72 = 10.72
d) Calculate the effect on total body clearance in a patient with stenosis (FR = 0.3).
Clr*/Clr = (1)(.3)/.3 + .6(1 - .3) = .3/.72 = .417
TBC = 18.8 + .417 = 19.22
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Oral Dosing
(hours)
Hygroton@Generic
.5
0.14
0.15
0.51
0.64
1.23
1.67
1.94
2.48
2.20
2.91
2.64
3.49
2.86
3.52
12
3.43
3.82
24
3.22
3.38
48
2.45
2.74
72
1.53
1.91
96
1.20
1.40
120
0.76
0.77
Pharmacokinetic parameters
Cpmax (mg) 3.73
4.62
336
Xu inf (mg)18.3
22.1
Ka (hr^-1)0.168
0.253
Ke (hr^-1)0.019
0.019
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Oral Dosing
Average mean83.1
84.5
blood presure
R(G/H)
Cpmax (mg) 1.23
outside
ok
Buspirone is a new anxiolytic agent that has been found to be effective for the
treatment of generalized anxiety disorder at a mean dose of approximately 20 mg/
day orally in divided doses. Buspirone is metabolized almost entirely. Less than
0.1% is found intact in the urine. The following data has been presented by Gammans (Am J Med:80(supp 3b),41-51;1986):
Time (hours)Concentration (ng/ml)
(hours)
1 mg I.V.20 mg oral
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Oral Dosing
0.25
--
1.07
0.50
4.33
1.76
1.0
3.75
2.45
2.80
2.51
2.10
2.05
1.57
1.60
0.8
0.91
a) find ka
b) Find Oral Peak Time and Oral Cmax.
c) Calculate the absolute bioavailability of buspirone.
answer:
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Oral Dosing
IV
Oral
13.9
Tmax (hr)
1.5
K (hr^-1)
0.290 0.289
ka (hr^-1)
1.3
/( 17.4/ 1
= 0.04
Valproate is a carboxylic acid anticonvulsant. Its activity may be related, at least
in part, to increase concentrations of the neurotransmitter inhibitor gamma aminobutyric acid in the brain. It is used alone or in combination with other anticonvulsants. in the prophylactic management of petit mal. It appears to be almost
entirely cleared by liver function with negligible amounts excreted into the urine
unchanged. It comes as soft gelatin capsules of 250 mg and enteric coated tablets
250 and 500 mg as well as oral syrup of 250 mg / 5 cc. Two different formulations of Valproate (250 mg) were prepared by Abbott and compared. The data is as
follows:
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Oral Dosing
Time(Hr.)Formulation BFormulation A
0.5
3.4
1.0
6.0
Ka = 0.7 hr^-1
1.5
7.9
Ke = 0.065 hr^-1
2.0
9.3
2.5
10.3
3.0
10.9
4.0
11.6
6.0
11.4
8.0
10.5
12.0
8.3
18.0
5.7
24.0
3.8
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Oral Dosing
need to respond to another health professional who asked you to stock that formulation for his patients.
6) Calculate the Total Body Clearance (TBC) of valproate.
Answers:
Formulation B
R(A/B)
= 0.493 hr^-1
= 0.0655
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Oral Dosing
Squibb
0.33
0.68
0.26
0.5
0.82
0.67
0.66
1.17
0.93
1.23
1.12
1.45
1.33
1.31
1.19
1.35
1.39
1.12
1.18
0.93
0.96
0.95
0.74
0.74
0.77
0.51
0.51
0.51
0.32
0.30
0.33
12
0.11
0.09
0.14
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I.V.
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Oral Dosing
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IV
LederleSquibb R(L/S)
AUC (0 to inf)8.577.46.8
1.09
Cpmax
1.8
1.28
1.25
1.02
Tmax
1.43
1.45
0.99
ka
---
1.51
1.93
t lag
0.24
/ 8.57
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= 0.86
Echizen and Eichelbaum (Clin Pkin 1986; 11:425-49) and Kleinbloesem et al (Clin
Pcol Therap 1986; 40: 21-8) Reviewed the pharmacokinetics of Nifedipine. While
the drug is not routinely given by IV bolus and does not strictly conform to a one
compartment model, lets treat the data as if those problems can be ignored. The
following data is offered for evaluation:
25mg IV
10 mg oral tablet
Formula AFormula B
Time Cp
Cp
Cp
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(hr.)
(mic/l)
(mic/l)
0.5
29.3
33.1
42.1
43.7
1.5
45.7
43.7
44.4
39.8
36.2
25.5
(mic/l)
139
3
4
65.6
27
20.7
31.1
13.6
9.9
14.6
6.5
4.7
1.5
1.0
12
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IV
R(A/B)
1.57
1.18 1.33
1.0
1.6
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I would not recomend tetracycline for a lactating mother. The dose that a nursing child gets from the milk
too high.
Oxazepam (acid, pKa 11.5) is an anxyolytic sedative with the usual adult dose 10
mg 3 times daily. If the circulating plasma concentration of oxazapam were 20
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mic/ml for nursing 120 lb mother, would her 9 lb infant be getting a comparable
mg per kg daily dose if he consumes 2 oz of his mothers milk every 2 hours. Prepare a short consult for her physician in which you might (or might not) recommend the patient stop breast feeding while she is on this medication. Include
appropriate calculations.
Conc AUC
Conc.
(hr)
(mg/L) (0->t)
(mg/L) (0->t)
(mg/L)
0.25
1.41
0.18
4.03
0.50
0.5
1.98
0.60
5.13
1.65
0.75
2.15
1.12
5.18
2.94
2.12
1.65
4.89
4.20
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1.56
3.49
3.37
8.33
0.764
1.05
4.80
2.26
11.14
0.512
0.707 5.67
1.51
13.03
0.343
0.318 6.70
0.68
15.22
0.154
0.143 7.16
0.306 16.20
0.069
AUC = D/(Vd * K)
Vd = D/(AUC * K)
= 50mg/(4.25 * 0.4)
= 29.4 L
Vd = 100mg/(7.48 * 0.4)
= 33.4 L
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E) 37.38
D) 1.14 E) 1.19
(7.48/100)/(4.25/50) = 0.88
E) 73.98
D) 1.14 E) 1.19
(16.9/200)/(4.25/50) = 1
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10) What is the absorption rate constant for the 100 mg tablet ?
A) 1.7 B) 2.2 *C) 2.6 D) 3.2 E) 3.7
11) What is the intercept of the extrapolated line for the 200 mg tablet ?
A) 3.5 B) 4.1 C) 5.6 D) 6.1 *E) 7.6
12) What is the absorption rate constant for the 200 mg tablet ?
A) 1.7 B) 2.2 C) 2.6 D) 3.2 *E) 4.01
15) Would you consider these two tablets bioequivalent (given normalization for
dose) (consider all ratios to be the 100 mg / 200 mg parameter normalized as to
dose where applicable)?
A) Yes
B) No, because the ratio of the ka's is 0.70
C) No, because the ratio of the AUCs is 0.44
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16) What infusion rate would you recommend to maintain an average plasma concentration of 1 mic/ml ?
A) 17.5 B) 13.3 *C) 11.8 D) 10.4 E) 9.0
17) What would be the concentration (mg/L) 2 hrs after discontinuing the infusion assuming you reached steady state ?
A) 0.67 B) 0.55 *C) 0.45 D) 0.37 E) 0.30
18) What is the Ratio of morphine concentration in the milk as compared to the
blood ?
A) 0.05 B) 0.5
C) 1
D) 2
*E) 20
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19) How much (mg) morphine is contained in 120 cc of breast milk (the child consumes 2 ounces every 2 hours)
*A) 1.2 B) 0.12 C) 0.06 D) 0.03 E) 0.003
20) In your professional judgment, will the child's dose cause a problem ?
A) No, morphine does not concentrate in the milk and thus the milk is ok to drink.
B) No, the dose is too small. The ratio of the child's dose to the mother's dose is
0.12.
C) Yes, even though the dose is small, we don't want any drug to get to the child.
*D) Yes, the dose is comparable to the mother's dose. The ratio of the child's to the
mother's dose is 1.2.
E) Not my job. I only give what the doctor orders.
Answers:
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IV
Tablet Tablet
0.89
Cpmax
1.7
2.15
5.23
0.82
Tmax
0.82
0.64
1.28
0.4
0.4
-.4
ka
---
2.76
4.01
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Answers are rounded off. When you pick a foil, use that number in subsequent calculations when needed.
Rifampin (unionized free base pKa 7.9) is a drug used to treat TB. The following
data was collected following a 600 mg oral tablet from the inovator (Treatment A),
and a 600 mg oral tablet from a generic (treatment B), and a 400 mg IV dose
(Treatment C).
Concentration (mic/mL)AUC(0->t)
TreatmentA
0.5
5.3
4.8
10.3
8.6
1.5
10.2
9.8
9.4
9.8
2.5
8.9
9.2
7.5
8.4
4.7
5.9
6.7
3.7
3.6
4.1
2.2
2.2
2.5
1.3
10
1.3
1.5
0.8
12
0.8
0.92
0.5
Time (hours)
1.2
7.8
4.55
9.15
6.1
14.05
18.8
AUC(0->inf)53.957.7
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(mic/mL*hr)
Lag time (min)18.610.5
Cp max10.6
9.9
Ka (hr^-1)2.66
a) 0
b) 7.8 *c) 10
d) 12
e) 15
Cp0 = AUC * K
= 39.8 * 0.25
= 9.95
a) 60
b) 51.3 *c) 40
Vd = D/Cp0
= 400mg/(9.95mg/L)
= 40.2 L
*a) 2.8
b) 2.3
c) 2.0
d) 1.75 e)
t1/2 = .693/0.25
= 2.77
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4) What is the elimination rate constant for rifampin (hr^-1)? *a) 0.25 b) 0.3 c)
0.35 d) 0.4 e) 0.45
*a) 2
b) 1.67 c) 1.43
0.5/0.25 = 2
7) Calculate the AUC (0->inf) for C (mic/mL*hr).
40 e) 60
a) 16
b) 26.85 c) 35
*d)
a) 0.70 *b)
(57.7/600)/(39.8/400) = 0.966
9) Calulate the comparative bioavailability for the generic product.
0.95 c) 1 *d) 1.05
a) 0.70 b)
e) 1.43
(57.7/600)/(53.9/600) = 1.07
10) Using Wagner-Nelson method, calculate the Ka for the generic product (hr^1). a) 0.45 b) 1 c) 1.55 d) 2 e) 2.45
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11) Calculate the peak time for the generic product (min).
91 e) 105
a) 37 b) 67 c) 86 d)
tp = [ln(Ka/K)]/(Ka - K)
= [ln(1.37/0.25)]/(1.37 - 0.25)
= 1.52 hr = 91 min
12) Calculate the peak time for the brand name product (min).
86 d) 95 e) 105
a) 37 *b) 59 c)
tp = [ln(2.66/0.25)]/(2.66 - 0.25)
= 0.98 hr = 59 min
13) Are the two products bioequivalent?
a) yes, all federal requirements are met.
*b) no, the ratio of the peak times are out side federal requirements.
c) no, the ratio of the lag times are out side federal requirements.
d) no, the ratio of the Kas are out side federal requirements.
e) no, the ratio of the comparative bioavailabilities are out side federal requirements.
14) What is the ratio of the concentration of milk (pH 6.1) to blood (pH 7.4)? a)
0.05 b) 0.05 c) 1 d) 15.4 *e) 20
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= 20
15) The average plasma concentration for the mother (110#) is 2.5 mg/L from a
600 mg once a day dosing regimen. If the baby (11#) drinks 780 mL of milk a day
(2 - 2.5 ounces every 2 hours), what is his daily dose (mg)?
a) 0.1 b) 0.13 c) 2
d) 30
*e) 39
Mother's blood average blood conc. is 2.5 mg/L therefore her milk conc. is 50
mg/L.
If the baby drinks 780 ml of milk he/she will get 39 mg of the drug.
16) Would you recommend mom stop breast feeding? (What % of the mom's daily
dose (mg/kg) is the baby's daily dose (mg/kg)?)
a) No, the child's dose is less than 1% of the mother's dose on a mg/kg/day basis.
b) No, the child's dose is about 5% of the mother's dose on a mg/kg/day basis.
c) Maybe, the child's dose is about 10% of the mother's dose on a mg/kg/day basis.
*d) Yes, the child's dose is about 50% of the mother's dose on a mg/kg/day basis.
e) Yes, the child's dose is about the same as the mother's dose on a mg/kg/day
basis.
17) While Rifampin is not administered by IV infusion, what would be the infusion rate necessary to maintain an average plasma concentration of 2.5 mg/L (mg/
hr)? *a) 25 b) 50 c) 100 d) 150 e) 200
Vd = D/Cp0
= 400/10.02
= 39.9 L
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Q = Cpss * K * Vd
= 2.5 * 0.25 * 39.9
= 25 mg/hr
18) While Rifampin is not administered by IV bolus, what would be the loading
dose necessary to obtain a plasma concentration of 2.5 mg/L (mg)? a) 25 b) 50
*c) 100 d) 150 e) 200
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IV
Tmax
1.27
1.7
0.25
0.25
0.25
ka
2.66
1.37
---
AUC
53.9
57.7
39.8
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Cpmax
10.6
9.9
10.02
(1) Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:
a}Cpss b}feathering c}Wagner-Nelson method d}clearance e}f
(2) For each of the following pairs of variables (ordinate against abscissa), draw
a graph illustrating the qualitative profile of their relationship. Where appropriate, indicate the nature of important slopes, intercepts, and values. Unless your
specifically indicate on your plot that semi-log paper is being considered (write "SL"), it will be assumed that rectilinear paper is being considered. Graphs are for a
drug given by oral route where applicable.
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a} total amount of drug collected minus the amount collected at the time in the
urine vs time
b} Plasma concentration of a drug given by oral route vs time
c} Plasma concentration of metabolite of a drug given by IV bolus vs time
d} Steady state plasma concentration vs infusion rate
e} Steaty state plasma consentration vs clearance
SECTION I
(1) Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:)
a}Cpss b}f c}Absolute Bioavailability d}Comparative Bioavailability
b} Treat-
(3) For each of the following pairs of variables (ordinate against abscissa), draw
a graph illustrating the qualitative profile of their relationship. Where appropriate, indicate the nature of important slopes, intercepts, and values. Unless your
specifically indicate on your plot that semi-log paper is being considered (write "SL"), it will be assumed that rectilinear paper is being considered. Graphs are for a
drug given by oral route where applicable.
dXu/dt vs t for a drug given orally.
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SECTION I
1. Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:
a) clearance b)f c) absolute bioavailability d) comparative bioavailability e)
AUC
2. By means of an annotated phase diagram explain how freeze-dried pharmaceutical injectables are made.
3. For each of the following pairs of variables (ordinate against abscissa) draw a
graph illustrating the qualitative profile of their relationship. Where appropriate,
indicate the nature of important slopes, intercepts, and values. Unless you specifically indicate on your plot that semi-log paper is being considered (write "SL"), it
will be assumed that rectilinear paper is being considered.
Pharmacological Response vs time
Peak time vs ka for oral dose
Fractional change in total body clearance vs. renal clearance
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AUC vs ka
AUC vs ke
SECTION I
1. Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:
a) first pass effect b) f c) Intrinsic clearance
d) comparative bioavailability e) Extraction ratio
3. For each of the following pairs of variables (ordinate against abscissa) draw a
graph illustrating the qualitative profile of their relationship. Where appropriate,
indicate the nature of important slopes, intercepts, and values. Unless your specifically indicate on your plot that semi-log paper is being considered (write "S-L"),
it will be assumed that rectilinear paper is being considered
fractional change in total body clearance vs plasma flow for drugs having a large
extraction ratio.
Peak time vs ka for oral dose
Fractional change in total body clearance vs. hepatic clearance.
AUC vs ka
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AUC vs clearance
SECTION I
1. Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:
Henderson-Hasselbach relationship
Therapeutic alternatives
Therapeutic equivalents
comparative bioavailability
Extraction ratio
Briefly discuss generic substitution by the pharmacist. Include such topics as when
it might be admissable and the liabilities involved.
3. For each of the following pairs of variables (ordinate against abscissa) draw a
graph illustrating the qualitative profile of their relationship. Where appropriate,
indicate the nature of important slopes, intercepts, and values. Unless you specifically indicate on your plot that semi-log paper is being considered (write "S-L"),
it will be assumed that rectilinear paper is being considered
a)
fractional change in total body clearance vs fractional change in plasma
flow for drugs having a small extraction ratio.
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b)
c)
Fractional change in total body clearance vs. fractional change in hepatic
clearance for drugs having a large extration ratio.
d)
e)
SECTION I
1. Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:
a) Bioequivalance
b) Intrinsic Clearance
c) first pass effect
d) Henderson - Hasselbach equation
e) f
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a)
b)
c)
d)
TBC vs Fi(H) for a drug with a high extraction ratio in the liver.
e)
TBC vs Fr(H) for a drug with a high extraction ratio in the liver
3. For each of the following pairs of variables (ordinate against abscissa) draw a
graph illustrating the qualitative profile of their relationship. Where appropriate,
indicate the nature of important slopes, intercepts, and values. Unless you specifically indicate on your plot that semi-log paper is being considered (write "SL"), it
will be assumed that rectilinear paper is being considered
a)
fractional change in total body clearance vs fractional change in plasma
flow for drugs having a small extraction ratio.
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b)
c)
Fractional change in total body clearance vs. fractional change in intrinsic
hepatic clearance for drugs having a large extraction ratio.
d)
e)
3. For each of the following pairs of variables (ordinate against abscissa), draw a
graph illustrating the qualitative profile of their relationship. Where appropriate,
indicate the nature of important slopes, intercepts, and values. Unless you indicate
on your plot that semi-log paper is being considered (write SL), it will be assumed
that rectilinear paper is being considered. Graphs are for a drug given by an oral
delivery system where applicable.
a)
Cpss vs. K
b)
Cp vs. ka
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c)
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I. pharmaceutical alternatives
II. pharmaceutical equivalents
III. bioequivalents
6) The Federal guidelines for for bioequivalence require that the following pharmacokinetic parameters be within + 20 % of
the innovator's product:
I. AUC, Peak time, Cpmax
II. Ka, Ke
III. Vd
8) The peak time of a drug given by the oral route is dependent on:
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9) The slope of the terminal portion of the graph of the metabolite of a drug which
(the drug, not the metabolite) was given
by intravenous bolus injection could be:
I. - the elimination rate constant of the metabolite
II. - the elimination rate constant of the drug
III. - the absorption rate constant of the metabolite
10) Comparative bioavailability includes calculations of the ratio(s) of the following pharmacokinetic parameters of two
oral products (generic / Innovator) normalized for dose :
I. AUC (0 to Inf)
II. Peak time
III. Cpmax
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Where the are only three foils (possible quesses), please use K type system:
(NOTE: if foils are equivalent, all must be selected)
A) I ONLY
B) III ONLY
C) I AND II ONLY
D) II AND III ONLY
E) I, II, AND III
3) When calculating the AUC for an oral product using the trapezoidal rule, concentrations necessary to calculate the
first trapezoid are:
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I the intercept of the extrapolated line of the plasma vs. time profile.
II the concentration at time zero, Cp0
III the concentration at the first time point
4) When calculating the AUC for an IV product using the trapezoidal rule, concentrations necessary to calculate the
first trapezoid are:
I the intercept of the extrapolated line of the plasma vs. time profile.
II the concentration at time zero, Cp0
III the concentration at the first time point
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8) When considering ion trapping, comparing a drug which forms sulfate salts
distributing between mother's milk and
blood, the ratio of total drug in milk to total drug in blood (Rm/b) can be
I greater than one.
II one.
III less than one.
9) When considering ion trapping, comparing a drug which forms sodium salts
distributing between mother's milk and
blood, the ratio of total drug in milk to total drug in blood (Rm/b) can be
I greater than one.
II one.
III less than one.
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Cyclosporine A
(Problem 8 - 6)
Quigano, R., et al., "Effect of atropine of gastrointestinal motility and the bioavailability of cyclosporine A in rats", Drug Metabolism and Disposition, Vol. 21, No. 1, (1993), p. 141 - 143.
In this study rats with an average weight of 300 g were given either an IV bolus dose of cyclosporine A (CyA)
or an oral dose of CyA. Subsequently, doses of atropine were given; however, the data below is that which was gathered prior to atropine administration. A summary of the some of data obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Bioequivalence
Dose (mg/kg)
ug- hr
AUC ------ mL
ug- hr 2
AUMC ------ mL
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug
Cp0 --------
mL
Vd (L)
ug-
Cp at 1 hour ------ mL
f
ug
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
1.
MRT iv
2.
3.
t1 2
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4.
Cp 0
5.
Vd
6.
The plasma concentration ( Cp ) of cyclosporine A at 1 hour after the iv dose was given.
7.
8.
MRT oral .
10.
MAT oral
11.
12.
13.
Cp max , the maximum concentration of the oral dosage form given as a single dose.
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Fosinopril
(Problem 8 - 7)
Gehr, T., et al., "The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients", European Journal of Clinical Pharmacology, Vol. 45, No. 5, (1993), p. 431 - 436.
Fosinopril (MW 562.6) is a new Angiotension Converting Enzyme (ACE) Inhibitor used in the treatment of
hypertension. Following oral administration, fosinopril is rapidly and almost completely hydrolyzed to its pharmacologically active metabolite, fosinoprilate (MW 435.2). About 50% of the drug is excreted unchanged through the kidneys. In this study, patients received either 7.5 mg of fosinoprilat administered intravenously or 10 mg of fosinopril
administered orally. A summary of the some of data obtained from this experiment is given below.
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Bioequivalence
Dose (mg/kg)
ug- hr
AUC ------ mL
ug- hr 2
AUMC ------ mL
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug-
Cp0 ------ mL
Vd (L)
ug
Cp at 1 hour --------
mL
f
ug
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
MRT iv
2.
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3.
t1 2
4.
Cp 0
5.
Vd
6.
The plasma concentration ( Cp ) of fosinopril at 1 hour after the iv dose was given.
7.
8.
MRT oral .
10.
MAT oral
11.
12.
13.
Cp max , the maximum concentration of the oral dosage form given as a single dose.
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Verapamil
(Problem 8 - 8)
Rutledge, D., Pieper, J., and Mirvis, D., "Effects of chronic phenobarbital on verapamil disposition in humans", The Journal of
Pharmacology and Experimental Therapeutics, Vol. 246, No. 1, (1988), p. 7 - 13.
This study focused on the effects of phenobarbital, a hepatic-enzyme inducer, on verapamil. Seven healthy
male volunteers with an average weight of 78.8 kg participated in the study. The patients received either an single oral
verapamil dose of 80 mg or a single intravenous verapamil dose of 0.15 mg/kg over 3 minutes. A summary of the some
of data obtained from this experiment is given below.
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Bioequivalence
Dose (mg/kg)
ug- hr
AUC ------ mL
ug- hr 2
AUMC ------ mL
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug
Cp0 --------
mL
Vd (L)
ug-
Cp at 1 hour ------ mL
f
ug
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
1.
MRT iv
2.
3.
t1 2
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Oral Dosing
4.
Cp 0
5.
Vd
6.
The plasma concentration ( Cp ) of verapamil at 1 hour after the iv dose was given.
7.
8.
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Oral Dosing
Zidovudine
(Problem 8 - 9)
Trang, J., et al., "Zidovudine bioavailability and linear pharmacokinetics in female B6C3F1 mice", Drug Metabolism and Disposition Vol, 21 (1993), p.189 - 193.
Zidovudine (AZT) is a potent inhibitor of HIV-1 during viral replication. It has been approved for the treatment of AIDS. In this study a 30 mg/kg dose of AZT was given to mice either iv or orally. :A summary of the some
of data obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Bioequivalence
Dose (mg/kg)
ug- hr
AUC ------ mL
ug- hr 2
AUMC ------ mL
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug
Cp0 --------
mL
Vd (L)
ug-
Cp at 1 hour ------ mL
f
ug
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
1.
MRT iv
2.
3.
t1 2
4.
Cp 0
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Oral Dosing
5.
Vd
6.
The plasma concentration ( Cp ) of zidovudine at 1 hour after the iv dose was given.
7.
8.
MRT oral .
10.
MAT oral
11.
12.
13.
Cp max , the maximum concentration of the oral dosage form given as a single dose.
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CHAPTER 8
Bioavailability, Bioequivalence,
and Drug Selection
OBJECTIVES
1.
Given sufficient data to compare an oral product with another oral product or an
IV product, the student will estimate (III) the bioavailability (compare AUCs) and
judge (VI) professional acceptance of the product with regard to bioequivalence
(evaluate (VI) AUC, T p and ( Cp ) max ).
2.
The student will write (V) a professional consult using the above calculations.
3.
The student will be able to calculate (III) the absolute bioavailability of drug products.
4.
The student will be able to discuss (II) the various factors affecting bioavailability.
5.
The student will be able to discuss (II) the various methods of assessing bioavailablity.
6.
7.
The student will be able to enumerate (II) FDA requirements regarding bioequivalence.
8.
The student shall be able to utilize (III) the FDA Orange Book to make drug
product selections.
9.
The student shall be able to discuss (II) and utilize (III) reasonalble guidelines
regarding drug product selections.
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8.1.1
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(EQ 8-1)
(where AUCEV and AUCIV are, respectively, the area under the plasma concentration-time curve following the extravascular and intravenous administration of a
given dose of drug. Knowledge of F is needed to determine an appropriate oral
dose of a drug relative to an IV dose.
"Relative" or Comparative bioavailability refers to the availability of a drug
product as compared to another dosage form or product of the same drug given in
the same dose. These measurements determine the effects of formulation differences on drug absorption. The relative bioavailability of product A compared to
product B, both products containing the same dose of the same drug, is obtained by
comparing their respective AUCs.
AUC
RelativeBioavailabilty = ---------------A
AUC B
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(EQ 8-2)
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(EQ 8-3)
Drug Product
A Intravenous injection
100
50
40
The F for Product B and Product C is 50% (F = 0.5) and 40% (F = 0.4), respectively. However, when the two oral products are compared, the relative bioavailability of Product C as compared to Product B is 80%.
8.1.2
2.
3.
transfer of drug molecule across the membrane lining the gastrointestinal tract into the systemic
circulation.
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Any factor that affects any of these three steps can alter the drug's bioavailability
and thereby its therapeutic effect. While there are more than three dozen of these
factors that have been identified (19-38), the more significant ones are summarized
here.
The various factors that can influence the bioavailability of a drug can be broadly
classified as dosage form-related or patient-related. Some of these factors are
listed in Table 8-2 on page 5 and Table 8-3 on page 5, respectively.
TABLE 8-2 Bioavailability
Particle size
Amount of disintegrant
Crystalline structure
Amount of lubricant
Special coatings
Nature of diluent
Compression force
Physiologic factors
Food
Variations in pH of GI fluids
Fluid volume
Other drugs
Intestinal motility
Perfusion of GI tract
Presystemic and first-pass metabolism
Age, sex, weight
Disease states
The physical and chemical characteristics of a drug as well as its formulation are
of prime importance in bioavailability because they can affect not only the absorption characteristics of the drug but also its stability. Since a drug must be dissolved
to be absorbed, its rate of dissolution from a given product must influence its rate
of absorption. This is particularly the case for sparingly soluble drugs. All the factors listed in Table 8-2 on page 5 can alter the dissolution rate of the drug, its bioavailability, and ultimately, its therapeutic performance.
One of the more important factors that affects the dissolution rate of slowly dissolving substances is the surface area of the dissolving solid (39). Peak blood levels occurred much faster with the smaller particles than the larger ones, primarily
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as a result of their faster dissolution rate. Particle size can also have a significant
effect on AUC(40). Serum levels of phenytoin after administration of equal doses
containing micronized (formulation G) and conventional (formulation F) drug
were measured. Based on the AUC, almost twice as much phenytoin was
absorbed after the micronized preparation (40).
There are numerous reports of the effects of formulation and processing variables
on the dissolution of active ingredients from drug products; an apparently inert
ingredient may affect drug absorption. For example, magnesium stearate, a lubricant, commonly used in tablet and capsule formulations, is water-insoluble and
water-repellent. Its hydrophobic nature tends to retard drug dissolution by preventing contact between the solid drug and the aqueous GI fluids. Thus, increasing the amount of magnesium stearate in the formulation results in a slower
dissolution rate of the drug, and decreased bioavailability(34) .
The nature of the dosage form itself may have an effect on drug absorption characteristics. The major pharmaceutical dosage forms for oral use are listed in Table 84 on page 6 in order of decreasing bioavailability of their active ingredients. The
decreasing bioavailability is related to the number of steps involved in the absorption process following administration. The greater the number of steps a product
must undergo before the final absorption step, the slower is the availability and the
greater is the potential for bioavailability differences to occur. Thus, solutions
(elixirs, syrups, or simple solutions) generally result in faster and more complete
absorption of drug, since a dissolution step is not required. Enteric-coated tablets,
on the other hand, do not even begin to release the drug until the tablets empty
from the stomach, resulting in poor and erratic bioavailability.
TABLE 8-4 Bioavailability
Fastest availability
Solutions
Suspensions
Capsules
Tablets
Coated tablets
Slowest availability
Controlled-release formulations
Bioavailability studies with pentobarbital from various dosage forms show the
absorption rate of pentobarbital after administration in various oral dosage forms
decreased in the following order: aqueous solution > aqueous suspension of the
free acid > capsule of the sodium salt > tablet of the free acid (41).
In addition to the dosage form-related factors identified above, bioavailability may
also be affected by a variety of physiologic and clinical factors related to the
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availability of some drugs have been observed. These can often be attributed to
individual variations in such factors as GI motility, disease state and concomitantly-administered food or drugs.
One example of the myriad of physiologic factors that can affect the bioavailability
of an orally-administered drug is a patient's gastric emptying rate. Since the proximal small intestine is the optimum site for drug absorption, a change in the stomach emptying rate is likely to alter the rate, and possibly the extent, of drug
absorption. Any factor that slows the gastric emptying rate may thus prolong the
onset time for drug action and reduce the therapeutic efficacy of drugs that are primarily absorbed from the small intestine. In addition, a delay in gastric emptying
could result in extensive decomposition and reduced bioavailability of drugs that
are unstable in the acidic media of the stomach (e.g. penicillins and erythromycin).
Differences in stomach emptying among individuals have been implicated as a
major cause of variations in the bioavailability of some drugs, particularly those
with acid-resistant enteric coatings. In a study (42), after the administration of 1.5
g acetaminophen to 14 patients, the maximum plasma concentration ranged from
7.4 to 37 mcg/ml, and the time to reach the maximum concentration ranged from
30 to 180 minutes. Both these parameters of bioavailability were linearly related
to the gastric emptying half-life found in each patient.
There are numerous factors that affect gastric emptying rate (Table 8-5 on page 8)
(43). Factors such as a patient's emotional state, certain drugs, type of food
ingested and even a patient's posture can alter the time course and extent of drug
absorption.
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TABLE 8-5
INFLUENCE ON GASTRIC
EMPTYING RATE
FACTOR
Increased viscosity of stomach contents
decreased
Body position
lying on left side
decreased
Emotional state
stress
increased or decreased
depression
decreased
anxiety
increased
Activity, exercise
decreased
Type of meal
fatty acids, fats
decreased
carbohydrates
decreased
amino acids
decreased
pH of stomach contents
decreased
decreased
increased
increased
Disease states
gastric ulcers
decreased
Crohn's disease
decreased
hypothyroidism
decreased
hyperthyroidism
increased
Drugs
atropine
decreased
propantheline
decreased
narcotic analgesics
decreased
amitriptyline
decreased
metoclopramide
increased
Since drugs are generally administered to patients who are ill, it is important to
consider the effects of the disease process on the bioavailability of the drug. Disease states, particularly those involving the GI tract, such as celiac disease, Crohn's
disease, achlorhydria, and hypermotility syndromes can certainly alter the absorption of a drug (32). In addition, some diseases concerning the cardiovascular system and the liver may also alter circulating drug levels after oral dosing.
Drugs are frequently taken with food, and patients often use mealtimes to remind
them to take their medications. However, food can have a significant effect on the
bioavailability of drugs. The influence of food on drug absorption has been recog-
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nized for some time, and several reviews have been published on the influence of
food on drug bioavailability (30-32, 36, 44). Food may influence drug absorption
indirectly, through physiological changes in the GI tract produced by the food,
and/or directly, through physical or chemical interactions between the drug molecules and food components. When food is ingested, stomach emptying is delayed,
gastric secretions are increased, stomach pH is altered, and splanchnic blood flow
may increase. These may all affect bioavailability of drugs. Food may also interact directly with drugs, either chemically (e.g. chelation) or physically, by adsorbing the drug or acting as a barrier to absorption. In general, gastrointestinal
absorption of drugs is favored by an empty stomach, but the nature of drug-food
interactions is complex and unpredictable; drug absorption may be reduced,
delayed, enhanced or unaffected by the presence of food. Table 8-6 on page 9
summarizes some of the studies that have indicated the effect of food on the bioavailability of a variety of drugs.
TABLE 8-6
Reduced Absorption
Delayed Absorption
Increased Absorption
Ampicillin
Acetaminophen
Chlorothiazide
Aspirin
Aspirin
Diazepam
Atenolol
Cephalosporins (most)
Griseofulvin
Captopril
Diclofenac
Hydralazine
Erythromycin
Digoxin
Labetalol
Ethanol
Furosemide
Metoprolol
Hydrochlorothiazide
Nitrofurantoin
Nitrofurantoin
Penicillins
Sulfadiazine
Propranolol
Tetracyclines (most)
Sulfisoxazole
Riboflavin
Source: Ref. 32
The effect of food and type of diet on the bioavailability of erythromycin is shown
in a study by Welling (45). The absorption of the antibiotic is significantly
reduced when it is administered with food compared with its absorption under fasting conditions. This reduced absorption is primarily a result of degradation of the
acid-labile erythromycin due to prolonged retention in the stomach.
Delayed absorption due to food has been demonstrated in the case of cephradine in
a study by Mischler (46). Similar results have been observed with other oral cephalosporins.
Some drugs demonstrate enhanced bioavailability in the presence of food. This
has been attributed to a variety of factors, including improved compound solubility
and more time for dissolution because of delayed gastric emptying. In the case of
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basis of studies performed with healthy human volunteers. These studies are generally performed under tightly-controlled fasting conditions in the absence of other
drugs. In practice, however, drugs are seldom taken under such ideal conditions,
and the factors leading to changes in drug absorption must be taken into consideration.
8.1.3
In-vivo methods
One method for assessing the bioavailability of a drug product is through the demonstration of a clinically significant effect. However, such clinical studies are
complex, expensive, time-consuming and require a sensitive and quantitative measure of the desired response. Further, response is often quite variable, requiring a
large test population. Practical considerations, therefore, preclude the use of this
method except in initial stages of development while proving the efficacy of a new
chemical entity.
Quantification of pharmacologic effect is another possible way to assess a drug's
bioavailability. This method is based on the assumption that a given intensity of
response is associated with a particular drug concentration at the site of action;
e.g., variation of miotic response intensity can be directly related to the oral dose
of chlorpromazine. However, monitoring of pharmacologic data is often difficult,
precision and reproducibility are difficult to establish, and there are only a limited
number of pharmacologic effects (e.g. heart rate, body temperature, blood sugar
levels) that are applicable to this method.
Because of these limitations, alternative methods have been developed to predict
the therapeutic potential of a drug. The current method to assess the clinical performance of a drug involves measurement of the drug concentrations in the blood
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Blood level studies are the most common type of human bioavailability studies,
and are based on the assumption that there is a direct relationship between the concentration of drug in blood or plasma and the concentration of drug at the site of
action. By monitoring the concentration in the blood, it is thus possible to obtain
an indirect measure of drug response. Following the administration of a single
dose of a medication, blood samples are drawn at specific time intervals and analyzed for drug content. A profile is constructed showing the concentration of drug
in blood at the specific times the samples were taken . The key parameters to note
are:
1.
AUC
, The area under the plasma concentration-time curve, The AUC is proportional to the
total amount of drug reaching the systemic circulation, and thus characterizes the extent of
absorption.
2.
Cmax , The maximum drug concentration. The maximum concentration of drug in the plasma
is a function of both the rate and extent of absorption. Cmax will increase with an increase in
the dose, as well as with an increase in the absorption rate.
3.
Tmax , The time at which the Cmax occurs. The Tmax reflects the rate of drug absorption, and
decreases as the absorption rate increases.
Bioavailability (the rate and extent of drug absorption) is generally assessed by the
determination of these three parameters.
Since the AUC is representative of, and proportional to, the total amount of drug
absorbed into the circulation, it is used to quantitate the extent of drug absorption.
The calculation of AUC has been discussed in Chapter 4. A variety of pharmacokinetic methods have been suggested for the calculation of absorption rates (51-56).
For clinical purposes, it is generally sufficient to determine Cmax and Tmax. If all
other factors are constant, such as the extent of absorption and rate of elimination,
then Cmax is proportional to the rate of absorption and Tmax is inversely proportional to the absorption rate. Thus, the faster the absorption of a drug the higher
the maximum concentration will be and the less time it will take to reach the maximum concentration.
Urinary Excretion Data -
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time. These studies are based on the premise that urinary excretion of the
unchanged drug is directly proportional to the plasma concentration of total drug.
Thus, the total quantity of drug excreted in the urine is a reflection of the quantity
of drug absorbed from the gastrointestinal tract. Consider the following example:
two products, A and B, each containing 100 mg of the same drug are administered
orally. A total of 80 mg of drug is recovered in the urine from Product A, but only
40 mg is recovered from Product B. This indicates that twice as much drug was
absorbed from Product A as from Product B. (The fact that neither product
resulted in excretion of the entire dose might be due to the existence of other routes
of elimination, e.g. metabolism).
This technique of studying bioavailability is most useful for those drugs that are
not extensively metabolized prior to urinary elimination. As a rule-of-thumb,
determination of bioavailability using urinary excretion data should be conducted
only if at least 20% of a dose is excreted unchanged in the urine after an IV dose
(56). Other conditions which must be met for this method to give valid results
include:
1.
the fraction of drug entering the bloodstream and being excreted intact by the kidneys must
remain constant.
2.
collection of the urine has to continue until all the drug has been completely excreted (five times
the half-life 1).
Urinary excretion data are primarily useful for assessing extent of drug absorption,
although the time course for the cumulative amount of drug excreted in the urine
can also be used to estimate the rate of absorption. In practice, these estimates are
subject to a high degree of variability, and are less reliable than those obtained
from plasma concentration-time profiles (57). Thus, urinary excretion of drug is
not recommended as a substitute for blood concentration data; rather, these studies
should be used in conjunction with blood level data for confirmatory purposes.
Single-dose versus
Multiple-Dose-
Most bioavailability evaluations are made on the basis of single-dose administration. The argument has been made that single doses are not representative of the
actual clinical situation, since in most instances, patients require repeated administration of a drug. When a drug is administered repeatedly at fixed intervals, with
the dosing frequency less than five half-lives, drug will accumulate in the body and
eventually reach a plateau, or a steady-state
At steady-state, the amount of drug eliminated from the body during one dosing
interval is equal to the available dose (rate in = rate out); therefore, the area under
the curve during a dosing interval at steady-state is equal to the total area under the
curve obtained when a single dose is administered. This AUC can therefore be
1.
Half life is defined as the length of time required to lose 50% of the drug in the body, assuming first order elimination.
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used to assess the extent of absorption of the drug, as well as its absolute and relative bioavailability.
Multiple-dose administration has several advantages over single-dose bioavailability studies, as well as some limitations. These are summarized in Table 8-8 on
page 14 (54, 59).
TABLE 8-8 Multiple
Advantages:
Eliminates the need to extrapolate the plasma concentration profiles to obtain the total AUC
after a single dose
Eliminates the need for a long wash-out period between doses
More closely reflects the actual clinical use of the drug
Allows blood levels to be measured at the same concentrations encountered therapeutically
Because blood levels tend to be higher than in the single-dose method, quantitative determination is easier and more reliable
Saturable pharmacokinetics, if present, can be more readily detected at steady-state
Limitations:
Requires more time to complete
More difficult and costly to conduct (requiring prolonged monitoring of subjects
Greater problems with compliance control
Greater exposure of subjects to the test drug, increasing the potential for adverse reactions
When a drug obeys linear, first-order kinetics, it is possible to estimate the results
that would be obtained during multiple dosing from single-dose studies. Projection is easily made with regard to the extent of absorption, using the AUC following a single dose. Results from bioequivalence studies indicate that conclusions on
the extent of absorption as assessed by the AUC can be made equally well on the
basis of a single or multiple dose study (60). Assessing the rate of absorption during multiple-dosing from single-dose studies has presented a greater problem.
Although a number of single-dose characteristics have been suggested as indicators of rate of absorption during multiple dosing (e.g. percent peak-trough fluctuation and percent peak-trough swing), results of bioequivalence studies indicate that
only the plateau time (the time during which the concentration exceeds 75% of the
maximum concentration, t 75% Cmax) and the residual concentration at the end of
the dose interval produce consistent results in assessing the rate of absorption in
single- and multiple-dose studies (54, 61).
In the case of drugs exhibiting nonlinear kinetics, establishing a linear relationship
between single- and multiple-dose bioavailability data has proven to be a difficult
task. Thus, it has been recommended that for drugs with either saturable elimination or a nonlinear first-pass effect, steady-state studies be carried out to assess
their bioavailability (62).
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8.1.4
STUDY DESIGN
Bioavailability studies involve the administration of the test dosage form to a panel
of subjects, after which blood and/or urine samples are collected and analyzed for
drug content. Based on the concentration profile of the drug, a judgement is made
regarding the rate and extent of absorption of the drug. Normally, the study is conducted in a group of healthy, male subjects who are of normal height and weight,
and range in age from 18 to 35 years (6). Questions have been raised regarding the
extent to which such a population reflects the performance of a given drug product
in a actual patient population. At first glance, it would seem that bioavailability
should be determined in patients actually suffering from the disease for which the
drug is intended, or in patients representative of the age and sex of subjects who
would be using the drug. However, there are several very good reasons for using
healthy volunteers rather than patients. In bioavailability studies, it is assumed
that there are no physiologic changes in the subjects during the course of the study.
If actual patients were used, this would not be a valid assumption, due to possible
changes in the disease state. Another potential problem with using patients is that
many patients take more than one drug. This could result in a drug-drug interaction which could influence the bioavailability of the test drug. In addition, diet and
fluid volume intake, both of which can influence a drug's bioavailability are more
difficult to control in a patient population than in a panel of healthy test subjects.
In general, it is more difficult with patients to have a standardized set of conditions
which are necessary for a dependable bioavailability study. However, it must be
recognized that factors that may affect a drug's performance in a patient population
may not be detected in a group of healthy subjects. Thus, it is best to conduct a
separate study in patients to determine if the disease, for which the drug is intended
to be used, alters the bioavailability of the drug.
Other important considerations in the methodology of a bioavailability study are
sample size, period of trial, and sampling. For statistical purposes, twelve subjects
are considered to be a minimum sample size. Otherwise there will not be enough
data to draw valid conclusions (63). The bioavailability testing period should be of
a sufficient length of time to ensure that drug absorption has been completed. This
length of time is at least three times the half-life of the drug; generally a period of
four to five times the half-life is used (63, 64). Blood samples should be taken
with sufficient frequency to permit an accurate determination of tmax, Cmax and
AUC.
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availability of the drug from that dosage form. The term commonly used to
describe this relationship is "in-vitro/in-vivo correlation" (65). Specifically, it is
felt that if such a correlation could be established, it would be possible to use
in-vitro data to predict a drug's in-vivo bioavailability. This would drastically
reduce, or in some cases, completely eliminate the need for bioavailability tests.
The desirability for this becomes clear when one considers the cost and time
involved in bioavailability studies as well as the safety issues involved in administering drugs to healthy subjects or patients. It would certainly be preferable to be
able to substitute a quick, inexpensive in-vitro test for in-vivo bioavailability studies. This would be possible if in-vitro tests could reliably and accurately predict
drug absorption and reflect the in-vivo performance of a drug in humans.
Disintegration Tests-
The early attempts to establish an indicator of drug bioavailability focused on disintegration as the most pertinent in-vitro parameter. The first official disintegration test appeared in the United States Pharmacopeia (USP) in 1950. However,
while it is true that a solid dosage form must disintegrate before significant dissolution and absorption can occur, meeting the disintegration test requirement only
insures that the dosage form (tablet) will break up into sufficiently small particles
in a specified length of time. It does not ensure that the rate of solution of the drug
is adequate to produce suitable blood levels of the active ingredient. Therefore,
while the test for tablet disintegration is very useful for quality control purposes in
manufacturing, it is a poor index of bioavailability.
Dissolution Tests-
Since a drug must go into solution before it can be absorbed, and since the rate at
which a drug dissolves from a dosage form often determines its rate and/or extent
of absorption, attention has been directed at the dissolution rate. It is currently
considered to be the most sensitive in-vitro parameter most likely to correlate with
bioavailability.
There are two official USP dissolution methods: Apparatus 1, (basket method),
and Apparatus 2 (paddle method). For details of these dissolution tests, the reader
is recommended to consult USPXXII/NFXVII (66).
Dissolution tests are an extremely valuable tool in ensuring the quality of a drug
product. Generally, product-to-product variations are due to formulation factors,
such as particle size differences, excessive amounts of lubricant and coatings.
These factors are reactive to dissolution testing. Thus, dissolution tests are very
effective in discriminating between and within batches of drug product(s). The
dissolution test, in addition, can exclude definitively any unacceptable product.
Limitations of
dissolution tests-
There are, however, problems with in-vitro dissolution testing which should be
noted - problems which make correlation with in- vivo availability difficult. The
first is related to instrument variance and the absence of a standard method. The
tests described in the USP are but a few of the large number of dissolution methods
proposed to predict bioavailability. Since the dissolution rate of a dosage form is
dependent on the methodology used in the dissolution test, changes in the appara-
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tus, dissolution medium, etc., can dramatically modify the results. Table 8-9 on
page 17 lists some of the factors related to the dissolution testing device that can
affect the dissolution rate of the drug.
TABLE 8-9
1. Degree of agitation
2. Size and shape of container
3. Composition of dissolution medium
pH
ionic strength
viscosity
surface tension
4. Temperature of dissolution medium
5. Volume of dissolution medium
6. Evaporation
7. Hydrodynamics (flow pattern)
Source: Ref. 67
Another significant problem is related to the difference between the in-vitro and
in-vivo environments in which dissolution occurs. In-vitro studies are generally
carried out under controlled conditions in one, or perhaps two, standardized solvents. The in-vivo environment (the gastrointestinal tract), on the other hand, is a
continuously changing, complex environment. There are many variables which
can affect the dissolution rate of a drug in the gastrointestinal tract, including pH,
enzyme secretions, surface tension, motility, presence of other substances and
absorption surfaces (68). Thus, drugs frequently dissolve in the body at rates quite
different from those observed in an in-vitro test situation. Most of the official dissolution tests tend to be acceleration dissolution tests which bear limited or no
relationship with in-vivo dissolution.
Adding to the complexity of correlating dissolution with in-vivo absorption are
factors such as drug-drug interactions, age, food effects, health, genetic background, biorhythm and physical activity (32, 69). All these factors may have an
effect on the rate and extent of absorption of a drug. Thus, the in-vivo environment is far more complex, variable, and unpredictable than any in-vitro test environment, making in-vitro / in-vivo correlations very difficult. A simple dissolution
test in a standardized vehicle cannot reflect the in vivo absorption of a drug across a
population (70).
Parameters used-
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drug in in- vitro and the bioavailability of a drug in-vivo. The in-vitro - in-vivo
correlative methods used most often are of the single-point type where the dissolution rate (expressed as the percent of drug dissolved in a given time, or the time
required for a given percent of the drug to dissolve) is correlated to a certain
parameter of the bioavailability. Examples of in-vivo parameters used include
Cmax, AUC, time to reach half-maximal plasma concentration, the average
plasma concentration after 0.5 or 1 hour, maximum urinary excretion rate, and
cumulative percent excreted in urine after a given time (71- 78). According to
Wagner, the best in-vitro variable to use is the time for 50 percent of the drug to
dissolve, and the best variable from in-vivo data to use is the time for 50 percent of
the drug to be absorbed (79).
Ideally, one would hope to find a linear relationship between some measurement of
the dissolution test and some measurement based on bioavailability studies.
Unfortunately, most attempts to accomplish this objective have failed.
8.1.6
IN-VITRO / IN-VIVO CORRELATION STUDIESThere have been many attempts to establish in-vitro / in-vivo correlations for a
large variety of drugs. Some of these studies have been summarized by Welling,
Banakar, and Abdou (71, 80-82).
While there are many published examples of satisfactory correlations between
absorption parameters and in-vitro dissolution tests, most studies have resulted in
poor, or moderate, in-vitro - in-vivo correlations, often involving agreement with
only one of the critical bioavailability parameters. Moreover, the positive correlations that have been found generally apply only to the specific formulation studied.
There have been instances where the dissolution rates or various formulations of
the same drug have been significantly different, yet little or no difference was
observed in their bioavailability parameters (83-85). There have also been cases
where a drug has failed to meet compendia dissolution standards but has demonstrated adequate bioavailability (86). Welling states: "To the writer's knowledge,
there have been no studies that have accurately correlated in- vitro and in-vivo data
to the point that the use of upper and lower limits for in-vitro dissolution parameters can be confidently used to predict in-vivo behavior and, therefore, to replace
in-vivo testing" (71).
Even if an in-vitro test could be designed that would accurately reflect the dissolution process in the gastrointestinal tract, dissolution is only one of many factors
that affect a drug's bioavailability. For example, saturable presystemic metabolism
may affect the extent of drug absorption, but this would not be predicted by an
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in-vitro test. Dissolution studies also would not predict poor bioavailability due to
instability in gastric fluid or complexation with another drug or food component.
Thus, the ultimate evaluation a drug product's performance under the conditions
expected in clinical therapy must be an in-vivo test; a dissolution test is unlikely to
entirely replace bioavailability testing (70, 87, 88). In-vitro methods are important
in the development and optimization of dosage forms while in-vivo tests are essential in obtaining information on the behavior of medication in living organisms.
One cannot be substituted for the other (69).
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8.2 Bioequivalence
Definitions
With the phenomenal increase in the availability of generic drugs in recent years,
the issues of bioavailability and bioequivalence have received increasing attention.
In order for a drug product to be interchangeable with the pioneer (innovator or
brand name) product, it must be both pharmaceutically equivalent and bioequivalent to it. According to the FDA, "pharmaceutical equivalents" are drug products
that contain identical active ingredients and are identical in strength or concentration, dosage form, and route of administration (89). However, pharmaceutical
equivalents do not necessarily contain the same inactive ingredients; various manufacturers' dosage forms may differ in color, flavor, shape, and excipients. The
terms "pharmaceutical equivalents" and "chemical equivalents" are often used
interchangeably.
"Bioequivalence" is a comparison of the bioavailability of two or more drug products. Thus, two products or formulations containing the same active ingredient are
bioequivalent if their rates and extents of absorption are the same. When a new
formulation of an existing drug is developed, its bioavailability is generally evaluated relative to the standard formulation of the originator. Indeed, a bioequivalence trial against the standard formulation is the key feature of an Abbreviated
New Drug Application (ANDA) submitted to the Food and Drug Administration
by a manufacturer who wishes to produce a generic drug. For a generic drug to be
considered bioequivalent to a pioneer product, there must be no statistical differences (as specified in the accepted criteria) between their plasma concentration-time profiles. Because two products rarely exhibit absolutely identical
profiles, some degree of difference must be considered acceptable, as will be discussed later.
Since the concentration of a drug in blood is used as an assessment of its clinical
performance, inherent in the demonstration that two preparations containing
equivalent amounts of the same drug produce similar concentrations of the drug
entity in blood is the assumption that they will elicit equivalent drug responses.
Thus, two products that are deemed to be bioequivalent are also assumed to be
therapeutically equivalent, and therefore interchangeable. This principle is fundamental to the concept of bioequivalence and is the basic premise on which it is
founded.
In general, the FDA considers two products to be "therapeutic equivalents" if they
each meet the following criteria (90):
1.
2.
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Background
3.
they are in compliance with compendial standards for strength, quality, purity and identity,
4.
5.
they have been manufactured in compliance with Good Manufacturing Practices as established
by the FDA.
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aminophylline
amphetamines
acetaminophen
(sustained-release)
codeine
ampicillin
ferrous sulfate
bishydroxycoumarin
chloramphenicol
hydrochlorothiazide
digoxin
chlorpromazine
ephedrine
dipheylhydantoin (phenytoin)
digitoxin
isoniazid
para-aminosalicylic acid
erythromycin
meprobamate
prednisolone
griseofulvin
penicillin VK
prednisone
oxytetracycline
sulfisoxazole
quinidine
penicillin G (buffered)
warfarin
pentobarbital
phenylbutazone
phenacetin
potassium chloride (solid dosage
forms)
salicylamide
secobarbital
sulfadiazine
tetracycline
tolbutamide
The concern about the bioinequivalence of some drugs led to the establishment in
1974 of the Drug Bioequivalence Study Panel of the Office of Technology Assessment (OTA). The objective was to ensure that drug products of the same physical
and chemical composition would produce similar therapeutic effects. Among the
11 recommendations of the Panel was the conclusion that not all chemical equivalents were interchangeable, but the goal of interchangeability was achievable for
most oral drug products (101). The Report recommended that a system should be
organized as rapidly as possible to generate an official list of interchangeable drug
products. The OTA Report, as well as the growing awareness within the scientific
and regulatory communities of bioavailability problems with marketed drug products, focused the attention of the FDA on bioequivalence and bioavailability problems and issues.
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8.2.1
BIOEQUIVALENCE REGULATIONS
In 1977, the FDA implemented a series of bioavailability and bioequivalence regulations which formed the basis of subsequent discussion, if not controversy, of
therapeutic equivalency of drug products (102). The regulations are divided into
two separate regulations; Subpart B - Procedures for Determining the Bioavailability of Drug Products and Subpart C - Bioequivalence Requirements. While
Table 11 summarizes the key provisions of the bioavailability regulations, those
for bioequivalence requirements are summarized in Table 8-11 on page 23.
TABLE 8-11 Key
1. Defines bioavailability in terms of both the rate and extent of drug absorption.
2. Describes procedures for determining the bioavailability of drug products.
3. Sets forth requirements for submission of in vivo bioavailability data.
4. Sets forth criteria for waiver of human in vivo bioavailability studies.
5. Provides general guidelines for the conduct of in vivo bioavailability studies.
6. Imposes a requirement for filing an Investigational New Drug Application.
Source: Ref. 103
The 1977 Bioequivalence regulations set forth the following criteria and evidence
supporting the establishment of a bioequivalence requirement for a given drug
product:
1.
Evidence from well-controlled clinical trials or controlled observations in patients that such
products do not give comparable therapeutic effects.
2.
Evidence from well-controlled bioequivalence studies that such products are not bioequivalent
drug products.
3.
Evidence that the drug products exhibit a narrow therapeutic ratio, (e.g., there is less than a
two-fold difference in the median lethal dose (LD50) and median effective dose (ED50) value
or have less than a two-fold difference in the minimum toxic concentration and minimum effective concentrations in the blood), and safe and effective use of the drug product requires careful
dosage titration and patient monitoring.
4.
Competent medical determination that a lack of bioequivalence would have a serious adverse
effect in the treatment or prevention of a serious disease or condition.
5.
The active drug ingredient has a low solubility in water--e.g., less than 5 mg/ml.
The dissolution rate of one or more such products is slow--e.g., less than 50 percent in
thirty minutes when tested with a general method specified by an official compendium or the
FDA.
b.
The particle size and/or surface area of the active drug ingredient is critical in determining
bioavailability.
c.
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Polymorphs, solvates, complexes, and such, exist that could contribute to poor dissolution
and may affect absorption.
d.
e.
There is a high excipient/active drug ratio present in the drug product--e.g., greater than 5
to 1.
The presence of specific inactive ingredients (e.g. hydrophilic or hydrophobic excipients)
that either may be required for absorption of the active drug or may interfere with such absorption.
f.
6.
Poor absorption of the drug, even when it is administered as a solution--e.g., less than 50
percent compared to an intravenous dose.
b.
c.
The drug is rapidly metabolized or excreted, requiring rapid dissolution and absorption for
effectiveness.
d.
The drug is unstable in specific portions of the gastrointestinal tract, requiring special
coatings and formulations--e.g., enteric coatings, buffers, film coatings--to ensure adequate
absorption.
e.
The drug follows nonlinear kinetics in or near the therapeutic range, and the rate and
extent of absorption are both important to bioequivalence.
f.
Types of Bioequivalence
Requirements
In the event that a drug meets one or more of the above six criteria, a bioequivalence requirement is established. The requirement could be either an in-vivo or an
in-vitro investigation, as specified by the FDA. The types of bioequivalence
requirements include the following:
1.
2.
An in-vivo test in animals that has been correlated with human in- vivo data.
3.
An in-vivo test in animals that has not been correlated with human in- vivo data.
4.
An in-vitro bioequivalence standard, i.e., an in-vitro test that has been correlated with human
in-vivo bioavailability data.
5.
A currently available in-vitro test (usually a dissolution rate test) that has not been correlated
with human in-vivo bioavailability data.
The regulations state that in-vivo testing in humans would generally be required if
there is well-documented evidence that pharmaceutical equivalents intended to be
used interchangeably meet one of the first three criteria used to establish a
bioequivalence requirement:
1.
2.
3.
The drug products exhibit a narrow therapeutic ratio (as described above), and safe and effective use of the product requires careful dosage titration and patient monitoring.
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The drug product is a solution intended solely for intravenous administration, and contains the
active drug ingredient in the same solvent and concentration as an intravenous solution that is
the subject of an approved full New Drug Application (NDA).
2.
The drug product is a topically applied preparation intended for local therapeutic effect.
3.
The drug product is an oral dosage form that is not intended to be absorbed, e.g., an antacid.
4.
The drug product is administered by inhalation and contains the active drug ingredient in the
same dosage form as a drug product that is the subject of an approved full NDA.
5.
The drug product is an oral solution, elixir, syrup, tincture or other similar soluble form, that
contains an active drug ingredient in the same concentration as a drug product that is the subject
of an approved full NDA and contains no inactive ingredient that is known to significantly
affect absorption of the active drug ingredient.
6.
The drug product is a solid oral dosage form (other than enteric-coated or controlled-release)
that has been determined to be effective for at least one indication in a Drug Efficacy Study
Implementation (DESI) notice and is not included in the FDA list of drugs for which in vivo
bioequivalence testing is required.
7.
The drug product is a parenteral drug product that is determined to be effective for at least one
indication in a DESI notice and shown to be identical in both active and inactive ingredients formulation, with a drug product that is currently approved in an NDA. (Excluded from the waiver
provision are parenteral suspensions and sodium phenytoin powder for injection.)
The drug product is one for which only an in-vitro bioequivalence requirement has been
approved by the FDA.
2.
The drug product is in the same dosage form, but in a different strength, and is proportionally
similar in its active and inactive ingredients to another drug product made by the same manufacturer and the following conditions are met:
a.
b.
both drug products meet an appropriate in-vitro test approved by the FDA
the applicant submits evidence showing that both drug products are proportionally similar
in their active an inactive ingredients.
c.
3.
The drug product is shown to meet an in-vitro test that assures bioavailability, i.e., an in-vitro
test that has been correlated with in-vivo data.
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4.
5.
The drug product is a reformulated product that is identical, except for color, flavor, or preservative, to another drug product made by the same manufacturer, and both of the following conditions are met:
a.
b.
both drug products meet an appropriate in vitro test approved by the FDA.
The drug product contains the same active ingredient and is in the same strength and dosage
form as a drug product that is the subject of an approved full NDA or Abbreviated New Drug
Application (ANDA) and both drug products meet an appropriate in-vitro test that has been
approved by the FDA.
Although the above list of criteria for waiver of an in-vivo bioavailability study is
quite lengthy, currently virtually all new tablet or capsule formulations from which
measurable amounts of drug or metabolites are absorbed into the systemic circulation require a human bioequivalence study for approval (104).
TABLE 8-12 Key
8.2.2
STUDY DESIGN
A single-dose bioequivalency study is generally performed in normal, healthy,
adult volunteers. The subject population should be selected carefully, so that product formulations, and not intersubject variations, will be the only significant determinants of bioequivalence (105). A minimum of 12 subjects is recommended,
although 18 to 24 subjects are used to increase the data base for statistical analysis.
The test and the reference products are usually administered to the subjects in the
fasting state (overnight fast for at least 10 hours, plus 2 to 4 hours after administration of the dose), unless some other approach is more appropriate for valid scientific reasons. These subjects should not take any other medication for one week
prior to the study or during the study. The bioavailability is determined by the collection of either blood samples or urine samples over a period of time and measurement of the concentration of drug present in the samples.
Generally, a crossover study design is used. Using this method, both the test and
the reference products are compared in each subject, so that inter-subject variables,
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such as age, weight, differences in metabolism, etc., are minimized. Each subject
thus acts as his own control. Also, with this design, subjects' daily variations are
distributed equally among all dosage forms or drug products being tested.
The subjects are randomly selected for each group and the sequence of drug
administration is randomly assigned. The administration of each product is followed by a sufficiently long period of time to ensure complete elimination of the
drug (washout period) before the next administration. The washout period should
be a minimum of 10 half-lives of the administered drug (106). A waiting period of
one week between administration is usually an adequate washout period of most
drugs.
With a drug requiring a washout period of one week, a typical randomized twoway crossover bioequivalency study is shown in Table 8-13 on page 27.
TABLE 8-13 Two
Treatment
Groupa
Week 1
I
II
a
A
B
Week 2
B
A
Assuming that the in-vivo performances of the two formulations are to be compared by examining their blood level profiles, one must be certain that an adequate
number of blood samples are taken. Blood samples should be drawn with sufficient frequency to provide an accurate characterization of the drug concentration-time profile from which tmax, Cmax and AUC can be determined. Typically,
a total of 10 to 15 sampling times might be required (107). Moreover, all samples
should be taken at the same time for both the test and the reference product to permit proper statistical analysis.
Additional features which contribute to good study design include:
1.
All drug samples obtained for the test and reference preparations should be analyzed by the
same method.
2.
Identical test conditions must be used for the two groups of subjects. For example, the types of
foods, fluid intake, physical activity, and posture should all be rigidly controlled in the study.
3.
The physical characteristics of the subjects (such as age, height, weight, and health) should be
standardized.
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Several important questions have been raised specifically regarding the design of
the bioequivalence tests. One of these deals with the selection of the appropriate
reference standard, since this is a critical component of a protocol (6, 108). Normally, the reference product is that available from the innovator company holding
the New Drug Application. However, in cases where there may be some question
as to the bioavailability of such a product, the study may utilize a solution of the
drug instead of or in addition to the marketed product. The use of a solution can,
of course, result in some difficulty in interpretation of the data: a solid dosage
form, when compared to a solution, will usually exhibit a lower Cmax and a longer
tmax. The clinical significance of these differences may be difficult to assess.
In some instances, the FDA must designate a specific product as the reference
standard from among two or more possible products; e.g., Proventil tablets, 4 mg
(Schering), not Ventolin tablets 4 mg (Allen and Hanburys), is the reference
product in bioequivalence studies of albuterol sulfate conventional tablets (108).
Advantages of Multipledose vs. single dose
studies:
Multiple-dosing eliminates the long washout periods required between single-dose administrations. The switch-over from one formulation to the other can take place in steady state.
2.
Single-dose studies may pose problems of sufficiently long sampling periods in order to get reliable estimates of terminal half-life, which is needed for correct calculation of the total AUC.
3.
Multiple-dose studies yield higher concentrations of drug in the blood, making accurate measurement easier. In addition, since drug concentrations need to be measured only over a single
dosing interval at steady state, the need to measure lower concentrations during a disposition
phase is avoided.
4.
Multiple-dosing studies can be conducted in patients, rather than healthy volunteers, allowing
the use of higher doses.
5.
Usually, smaller intersubject variability is observed in steady-state studies, which may permit
the use of fewer subjects.
6.
Thus, for some drug products, multiple-dose bioequivalence studies are appropriate and should be performed. In fact, according to one of the conclusions of the
Bio- International '92 conference on the bioequivalence of highly variable drugs, a
multiple-dose study is required in the case of compounds exhibiting nonlinear
pharmacokinetics (110). The circumstances under which a multiple-dose study
may be required are summarized in the regulations (109):
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1.
When there is a difference in the rate of absorption but not in the extent of absorption.
2.
3.
When the concentration of the active moiety in the blood resulting from a single dose is too low
for accurate determination.
4.
8.2.3
ASSESSMENT OF BIOEQUIVALENCE
In order for different formulations of the same drug substance to be considered
bioequivalent, they must be equivalent with respect to the rate and extent of drug
absorption. Thus, the two predominant issues involved in the assessment of
bioequivalence are: the pharmacokinetic parameters that best characterize the rate
and extent of absorption and, the most appropriate method of statistical analysis of
the data.
Pharmacokinetic criteria
Statistical criteria
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ence formulations. That is, one must determine whether the test and reference
products differ within a predefined level of statistical significance. Since the statistical outcome of a bioequivalence study is the primary basis of the decision for
or against therapeutic equivalence of two products, it is critically important that the
experimental data be analyzed by an appropriate statistical test.
In the early 1970s, bioequivalence was usually determined only on the basis of
mean data. Mean AUC and Cmax values for the generic product had to be within
+20% of those of the reference (innovator) product (108). Although the 20% value
was somewhat arbitrary, it was felt that for most drugs, a 20% change in the dose
would not result in significant differences in the clinical response to drugs (114).
A relatively common misconception is that current regulatory standards still allow
this difference of 20% in the means of the pharmacokinetic variables (Cmax and
AUC) of the test and reference formulations. The FDA's statistical criteria for
approval of generic drugs now requires the application of confidence limits to the
mean data, using an analysis known as the two one-sided tests procedure (115).
This change came about as a result of the conclusion of the FDA Bioequivalence
Task Force in 1986 that the use of a 90% confidence interval based on the two
one-sided t-tests approach was the best available method for evaluating bioequivalence (111).
Westlake was the first to suggest the use of confidence intervals as a means of testing for bioequivalence (116). Recognizing that no two products will result in identical blood-level profiles, and that there will be differences in mean values between
products, Westlake pointed out that the critical issue was to determine how large
those differences could be before doubts as to therapeutic equivalence arose (107,
117). A test formulation was considered to be bioequivalent to a reference formuCp max test
AUC test
lation if 0.8 < ------------------< 1.2 and 0.8 < -------------------< 1.2 . (119). By this proceAUC ref
Cp max ref
dure, if test and reference products were not bioequivalent (i.e. means differed by
more than 20%), there was a 5% chance of concluding that they are bioequivalent.
The current FDA guidelines are that two formulations whose rate and extent of
absorption differ by -20%/+25% or less are generally considered bioequivalent
(90). In order to verify that the -20%/+25% rule is satisfied, the two one-sided statistical tests are carried out: one test verifies that the bioavailability of the test
product is not too low and the other to show that it is not too high. The current
practice is to carry out the two one-sided tests at the 0.05 level of significance.
Computationally, the two one-sided tests are carried out by computing a 90% confidence interval. For approval of an ANDA, a generic manufacturer must show
that the 90% confidence interval for the ratio of the mean response (usually AUC
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and Cmax) of its product to that of the innovator is within the limits of 0.8 to 1.25.
Since these tests are carried out at the 0.05 level of significance, there is no more
than a 5% chance that they will be approved as equivalent if they differ by as much
or more than is allowed by the equivalence criteria (-20%/+25%).
Since this test requires that the 90% confidence interval of the difference between
the means be within a range of -20%/+25%, it is more stringent than simply requiring the comparison of the test and reference products' AUC and Cmax to be within
the 80 to 125% range. If the mean response of the generic product in the study
population is near 20% below or 25% above the innovator mean, one or both of the
confidence limits will fall outside the acceptable range and the product will fail the
bioequivalence test. Thus, the confidence interval requirement ensures that the
difference in mean values for AUC and Cmax will actually be less than -20%/
+25%. It should be pointed out that the standards vary among drugs and drug
classes. For example, antipsychotic agents may fall within a 30% variation and
antiarrhythmic agents may be allowed a 25% variation (122).
The actual differences between brand and generic products observed in bioequivalence studies have been reported to be small. The FDA has stated that for
post-1962 drugs approved over a two-year period under the Waxman-Hatch bill
(1984), the mean bioavailability difference between the generic and pioneer products has been about 3.5% (120). In addition, 80% of the generic drugs approved
by the FDA between 1984 and 1986 differed from the innovator products by an
observed difference of only +5%. Such differences are small when compared to
other variables of drug therapy and would not be expected to produce clinically
observable differences in patient response.
8.2.4
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At the center of the controversy were the methods and criteria used by the FDA to
determine bioequivalence. Assessment of bioequivalence was done on the basis of
mean data: mean AUC and Cmax values for the generic product had to be within
+20% of those of the innovator product for approval. A statistical test was
employed to assess the power of the test to detect a 20% mean difference in treatments. For drugs that could not meet the statistical criteria because of inherent
variability, another rule was used, the so-called "75/75" rule: that in at least 75%
of the subjects, the test formulation must fall within the range of 75% to 125% of
the reference standard to be considered equivalent (122). It was felt by many that
these rules permitted too much variability in the bioavailability of test drugs and
could result in therapeutic failure or increased risk of side effects (4, 15, 123).
Statistically, the power approach and the 75/75 rule were shown to have poor performance characteristics and bioequivalence evaluation based on these methods
was discontinued by the FDA in 1986. In their place, the Agency currently
employs the two one-sided tests procedure, as previously discussed.
Although the decision of bioequivalence is now made in a more statistically valid
way and the associated concerns have diminished somewhat, some important
questions and controversies in bioequivalence remain. These are primarily centered around study design, the criteria used to establish or refute equivalence, and
the assumption that products that are bioequivalent are therapeutically equivalent.
One criticism of bioequivalence testing is that it is almost always done in a panel
of young, healthy male volunteers rather than in the target population for which the
drug is intended. Clearly, the performance of a drug product in a 20-year-old male
will not be the same as in an 85-year-old woman. Serious concerns have been
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TABLE 8-15
Category
Example
Cardiovascular drugs
digoxin
Anticonvulsants
phenytoin
Bronchodilating agents
theophylline
Oral anticoagulants
warfarin
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8.2.5
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turers of generic drugs (134, 140, 147, 148). It was felt that this stringent FDA
review of generics proved the overall integrity of the companies that emerged with
a clean bill of health. After a sharp drop in the use of generic drugs in 1989, they
began to rise nearly as quickly as they fell, and by mid-1990, sales of generics
were approaching their previous record high (141).
This trend in generic drug utilization is expected to continue its upward spiral, with
newly generic drugs coming to market at an increasing rate. There are several factors that have contributed to this period of considerable growth in the generic drug
industry. One major factor was the passage of the Drug Price Competition and
Patent Term Restoration Act (Waxman-Hatch Act) in 1984. This act, by eliminating the requirement for clinical safety and efficacy testing for generics of drugs
introduced after 1962, greatly expedited the entry of generic drugs into the marketplace. The purpose of this act was to facilitate generic competition and thereby
reduce health care costs. This act significantly expanded the number of drugs eligible to be manufactured as generics. Another factor fueling the surge of generic
products is the abundance of brand name drugs whose patents began expiring in
1986. Between 1991 and 1994, patents expired on brand-name drugs whose combined annual sales totaled $10 billion (141). These include Procardia, Ceclor,
Tagamet, Cardizem, Feldene, Naprosyn, and Xanax. All told, more than
100 drugs worth upwards of $25 billion in sales will have come off patent by the
year 2000 (149). Table 8-16 on page 37 lists some recent and impending patent
expirations (150, 151). As a result of these patent expirations on popular drugs,
there has been an explosion of new generic drug applications.
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Brand Name
Procardia
Tenormin
Ceclor
Cardizem
Feldene
Naprosyn
Xanax
Tagamet
Seldane
Micronase
Capoten
Zantac
Trental
Noroxin
Generic Name
Nifedipine
Atenolol
Cefaclor
Diltiazem
Piroxicam
Naproxen
Alprazolam
Cimetidine
Terfenadine
Glyburide
Captopril
Ranitidine
Pentoxifylline
Norfloxacin
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8.2.6
all the drug products approved by the FDA as being safe and effective under the Federal Food,
Drug and Cosmetic Act, and
2.
2.the therapeutic equivalence evaluations for all approved multisource prescription drug products (those pharmaceutical equivalents available from more than one manufacturer).
8.2.7
THERAPEUTIC EQUIVALENCE
Drug products are considered to be therapeutic equivalents if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect when
administered to patients as specified in the labeling (90). In general, the FDA
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evaluates as therapeutically equivalent those drug products that satisfy the following general criteria:
1.
2.
b.
meet compendial and other applicable standards for quality, purity, strength and identity.
3.
They are bioequivalent. Bioequivalence may be established by either an in-vivo or in-vitro test,
depending on the drug. If the drug presents a known or potential bioequivalence problem then
an appropriate standard must be met which demonstrates a comparable rate and extent of
absorption.
4.
5.
They are manufactured in compliance with Current Good Manufacturing Practice regulations.
The FDA believes that drug products meeting the above criteria are therapeutically
equivalent and can be substituted with the full expectation that the substituted
product will produce the same therapeutic effect as the prescribed product.
8.2.8
THERAPEUTIC EQUIVALENCE EVALUATION CODESThe FDA uses a two-letter coding system for multisource products. The first letter
in the code allows users to determine whether a particular product has been evaluated therapeutically equivalent to other pharmaceutically equivalent products. The
second letter in the code provides additional information about the basis of FDA's
evaluation. The various categories are summarized in Table 8-17 on page 40.
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equivalency codes
Drug products the FDA does not consider to be therapeutically equivalent; i.e.
drug products for which actual or potential bioequivalence problems have not
1.
2.
designated as:
with specific dosage forms rather than with the active ingredient. These products
AA
AN
AO
AP
AT
Topical products
1.
2.
3.
BD
BE
BN
BP
BR
BS
BT
BX
B*
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There are two basic categories into which multisource drugs have been placed, "A"
or "B". Drug products rated "A" are products that the FDA considers to be therapeutically equivalent to the pharmaceutically equivalent original product. These
fall into one of two classes:
1.
2.
Actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in
vitro evidence supporting bioequivalence.
Category "B" consists of drug products that the FDA does not at this time consider
to be therapeutically equivalent to the pharmaceutically equivalent reference product. Certain types of products are rated B by virtue of their specialized dosage
forms. For example, controlled-release dosage forms are rated BC, unless
bioequivalence data have been submitted as evidence of equivalence. In this case,
the product would be coded AB.
The fact that a product is in the "B" category does not mean it should not be dispensed; it simply means that a B rated product should not be substituted for a pharmaceutically equivalent product. For example, glyburide is marketed as
Micronase and DiaBeta by two different manufacturers. Both these products
are clinically effective, but because bioequivalence between the two has not been
studied, they are B rated and are not interchangeable.
To avoid possible significant variations among generic drugs as a result of comparison to different reference drugs, the FDA began designating a single reference
listed drug against which all generic versions must be shown to be bioequivalent.
The reference listed drug is identified by the symbol "+" in the Prescription Drug
Product List. This symbol was used for the first time in the 1993 edition of the
Orange Book.
Limitations and
exclusions-
Although the Orange Book is a very valuable reference for pharmacists performing drug product selection, it has certain limitations, which must be recognized. It
was not intended to serve as a single comprehensive reference on all multisource
drugs. Many prescription drug products are not listed in the Orange Book, making
evaluation of their therapeutic equivalence difficult, if not impossible. Exclusion
of a drug from the Orange Book means that the FDA has not evaluated its safety,
efficacy and quality. Table 18 lists the classes of products excluded from the
Orange Book. Because the equivalence of these excluded products is unknown,
interchanging of these products should be avoided.
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1.
Drugs marketed before the passage of the Federal Food, Drug, and Cosmetic Act of 1938. These are not
included because the FDA has not reviewed these drugs for safety and efficacy and does not have the necessary
information to make therapeutic equivalence evaluations.
Examples: digoxin, morphine, codeine, thyroid, levothyroxine, phenobarbital and nitroglycerin
2.
3.
Drugs still undergoing Drug Efficacy Study Implementation (DESI) review. These are drugs that were
marketed between 1938 and 1962 on the basis of safety, but not efficacy. Although most of these drugs have
been reviewed and are listed in the Orange Book, there are still a number of these pre-1962 drugs which have
not yet been classified as "effective" under the DESI program, and are not listed.
Examples: nitroglycerin controlled-release capsules, pentaerythritol tetranitrate, isocarboxazid,
hydrocortisone-iodochlorhydroxyquin cream
In addition, nitroglycerin transdermal patches are still undergoing efficacy studies, and are not listed in the
Orange Book.
Another limitation of the Orange Book that all pharmacists should be aware of is
that the drug listings contain the names of only the companies that actually hold an
approved NDA or ANDA; they may not be the same as the actual manufacturer or
distributor. It is fairly common practice for a drug to be manufactured pursuant to
an NDA or an ANDA but distributed under license agreement by another company. In this instance, the distributor would not be listed in the Orange Book.
Since pharmacists are, understandably, generally unaware of the name of the actual
holder of the NDA or ANDA, it is often difficult for them to determine the therapeutic equivalence of a particular multisource product if it is not listed in the
Orange Book. For example, there are over thirty manufacturers and distributors
marketing approved, therapeutically equivalent versions of furosemide 40 mg tablets (154). However, only twelve of these companies are actually listed in the
Orange book, since these are the actual holders of an NDA or ANDA. Therefore,
the pharmacist would have to verify the therapeutic equivalence evaluation of the
non-listed products by obtaining the information from the manufacturer, packager,
or supplier.
Legal status and
pharmacists'
responsibility-
The Orange Book per se has no legal status. The FDA stresses that it is a source of
information and advice on drug product selection, but it does not mandate the drug
products which may be dispensed nor the products that should be avoided. Thus,
the Orange Book does not carry the weight of regulation or law, and the FDA
assumes no liability for drug products selected on the basis of its equivalence evaluation.
The Orange Book points out that "FDA evaluation of therapeutic equivalence in no
way relieves practitioners of their professional responsibilities in prescribing and
dispensing such products with due care." There are circumstances where pharma-
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cists will have to exercise professional care and sound judgement in selecting a
drug product for a particular patient. Although two products may be rated as being
therapeutically equivalent in the Orange Book, they may not be equally suitable
for a particular patient. Drugs that share the "A" code may still vary in ways that
could affect patient acceptance. They may differ in shape, color, taste, scoring,
configuration, packaging, preservatives, expiration time, and in some instances,
labeling. If products with such differences are substituted for each other, there is
potential for patient confusion or decreased patient acceptance. For example, a
patient may be sensitive to an inert ingredient in one product that another product
does not contain. Or, a patient may become confused if the color or shape of a
product varies from that to which he has become accustomed. A patient may reject
the administration of a substituted product because of differences in taste or
appearance. When such characteristics of a specific product are important in the
treatment of a particular patient, the pharmacist should select a product with these
considerations in mind as well as bioequivalence.
Despite its limitations and shortcomings, the Orange Book is a very useful guide
for rational product selection. Pharmacists can utilize the information presented
there, in combination with sound professional judgment, to make decisions on
behalf of their patients regarding the choice of the most appropriate drug product.
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Brand Selection
Year
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
Jan.-June 1993
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18
20
23
25
27
30
32
34
38
41
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8.3.1
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DISPENSING DECISIONS
? State Rules and Regulations. Pharmacists should be cognizant of legal requirements that address the issue of drug product selection. Many states have positive or negative
formularies to provide guidance in drug product selection.
? Bioequivalency Information/Orange Book Ratings. Only products with proven bioequivalency should be selected to be dispensed in lieu of the innovator product.
Products that are listed in the FDA's Approved Drug Products and Therapeutic Equivalence Evaluations (the Orange Book) as "A" rated should be selected when such products
are available. For pre-1938 drugs, the selection should be based on data obtained from the literature, because bioequivalency testing is not required by the FDA for these
drug products.
? Dosage Form. The type of dosage form should be considered whenever one drug product is selected from among multisource drug products. This is especially true with
extended or delayed release medications.
? Previous Drug Use. Two questions should be considered regarding previous drug product usage. First, is the prescribed drug a continuation of already successful therapy?
If it is, the impact of any change in source of the medication should be considered. The pharmacist should also know which product the patient was using previously, including
any medications in the hospital if the patient was recently discharged. Second, was the original product dispensed a generic product? If so, preference should be given to
continuing to dispense the same generic product from the same source.
? Patient Status. The pharmacist should consider how well controlled the patient is and how susceptible that patient might be to small changes in drug absorption. If a
patient has labile control or has experienced great difficulty in achieving control, the pharmacist should continue therapy with a product from a single source throughout therapy.
? Diseases. The seriousness of the disease and its potential impact on the patient may influence the pharmacist's willingness to change products.
? Drug Class or Category. Drugs with narrow therapeutic ranges and with known clinically significant bioavailability problems should be substituted with care and/or after
discussion with the prescriber.
? Cost. The cost of the product , while an important consideration, should be a secondary consideration in selecting among products judged by the pharmacist to be
bioequivalent.
? Patient Opinion. An informed patient, cooperating with a physician and pharmacist in his or her drug therapy, is an important element in ensuring the best possible
therapeutic outcomes. The pharmacist should take into account the patient's need when selecting from multisource drug products and inform the patient of any potential
consequences associated with alternate product selections.
PURCHASE DECISIONS
? Current State Laws and Regulations. Some states have positive or negative formulary systems that place regulatory restrictions on the products considered therapeutically
equivalent. The state formulary may not always be in agreement with classifications listed in the FDA's Orange Book. Therefore, pharmacists should be familiar with both.
? Bioequivalency Information/Orange Book. Products shown to be bioequivalent through reference to the Orange Book or other reliable source of bioequivalency
information are preferred. Purchase decisions for drugs marketed prior to 1938 should be based on data obtained from the literature or the manufacturer, because bioequivalency
testing may not be required by the FDA for these drug products.
? Drug Category. Greater attention should be given to purchasing strategies for drug products used for serious or life-threatening diseases and in situations where therapeutic
activity of the product is confined to a narrow range of biologic fluid concentration.
? Availability. A continuous supply from the same manufacturer is essential even in the event that the distributor has changed to ensure that refills of prescriptions will
contain the same product as originally dispensed. However, in those instances when the manufacturer of a generic drug product has to be changed, care should be exercised
to ensure that the new drug product is equivalent to the formerly stocked drug product.
? Supplier's Reputation. The reputation of the manufacturer in terms of its ability to adhere to good manufacturing practices (GMP) that ensure that each dosage form is
manufactured correctly and in a consistent manner is an important consideration. When purchasing a product from a distributor rather than directly from the manufacturer,
the procedure used by that supplier in selecting manufacturers for multisource products is also an important consideration. Establishment Inspection Reports and recall
reports are available from FDA through a Freedom of Information (FOI) request. These are valuable tools in this decision.
? Cost.
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of Multi-source Suppliers
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Pharmacists have the responsibility of correctly selecting and dispensing multisource products that will have the greatest likelihood of achieving a positive therapeutic outcome in a cost-effective manner. The more information pharmacists
have about a product and its manufacturer, the more likely they will be to make the
most appropriate choice. Price cannot be the single factor in selecting a product. It
is also clear, as Joseph Oddis stated, "Rational drug product selection entails far
more than simply consulting the FDA's Orange Book or looking at the price catalogue" (166).
8.3.2
SPECIAL CASES
While in most situations selection of drug products that are therapeutically equivalent can be done without undue complications, there are some circumstances
where problems could occur. Depending on the drug, its formulation, the disease
being treated, and the condition of the patient, generic substitution may not be
advisable. Some of these special situations require extra attention and handling by
the pharmacist.
There are a number of drugs that could present problems when interchanged.
Drugs that are poorly water soluble may have inherent problems with rate and
extent of dissolution, resulting in poor or variable bioavailability. Drugs that are
potent and thus present in very low amounts in a dosage form could present problems due to formulation factors. Some dosage forms may have inherent bioavailability problems, such as controlled-release products. And drugs which are
considered "critical" also need special consideration. "Critical" drugs have been
defined as drugs with a narrow therapeutic range, where a change in plasma concentration might result in adverse clinical outcome; drugs that are considered primarily for control of a disease rather than for alleviation of temporary symptoms;
and drugs that have inherent or historical bioavailability or bioequivalence problems (8, 19). Seven classes of drugs have been identified that have demonstrated
bioequivalence problems or, because of the nature of the product, have the potential for creating therapeutic problems if product interchange is permitted (Table 822 on page 51) (167-168).
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There have been numerous reports of drugs implicated in therapeutic problems due
to bioinequivalence difficulties. In addition to those in the categories given in
Table 8-22 on page 51, these include furosemide, propranolol, diazepam, prednisone, nitrofurantoin, and amitriptyline (20, 126, 167, 169-180). Although the
documentation implicating these drugs in therapeutic failures due to bioavailability problems is primarily anecdotal in nature (and thus disregarded by the FDA),
the performance of these products should still be closely observed and monitored,
and care should be taken when selecting drugs from these categories.
In addition to "critical" drugs, critical patients and critical diseases have also been
identified when special care should be taken in performing product selection (8,
166). Critical patients are the very old and the very young, those suffering from
multiple diseases who are managed with multiple drugs, and those who live alone,
making observation of adverse drug effects unlikely. Critical diseases are generally chronic in nature and difficult to stabilize, where drug-disease interactions can
present major problems (e.g. congestive heart failure, asthma, diabetes, cardiac
disorders, and psychoses). In all the above special "critical" circumstances, there
is a high risk of therapeutic problems, and product selection requires extra attention and precautions. In fact, product substitution and interchange in these cases is
generally discouraged. Once a product (brand or generic) has been selected for a
course of therapy, the pharmacist should not change to a different product if it can
be avoided. If interchange is performed, it should be done only with the utmost
care, and the patient should be monitored for any adverse outcomes.
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Pharmacist's
professional
responsibility-
Drug product selection has been and continues to be a primary and challenging professional responsibility of pharmacists. It is one where the pharmacist
must exercise professional care and sound judgement to make decisions on behalf
of the patient to maximize safety and efficacy, while minimizing cost. Pharmacists
have a professional obligation to patients to take whatever steps are necessary to
assure themselves that the medicines they are dispensing are safe and effective.
Although some of this activity is currently constrained by bureaucratic and regulatory restrictions that often discourage, or entirely prevent, individual professional
evaluation and initiative, with a greater appreciation and understanding of the scientific, clinical, and regulatory issues that form the basis of the process, pharmacists can make decisions that result in better patient care. Pharmacists must take
steps to ensure the quality and integrity of the drug products dispensed to their
patients. To accomplish this, pharmacists must look to pharmaceutical manufacturers to supply them with a quality product they can trust. Thus, the manufacturer
of a multisource product must be carefully selected to ensure that the products they
supply are of proper quality. If necessary, pharmacists should conduct independent
research into the reputation and integrity of the manufacturer, or, if products are
purchased through a buying group, should make sure that established policies and
guidelines are in place to review multisource products. When considering purchasing drug products, the pharmacist should request the manufacturer to provide
certain documentation and information, and should then evaluate this information
(see Table 23).
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all the currently available information in order to arrive at and render a decision
regarding the most appropriate product to use for a specific patient.
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8.4 Summary
With the dramatic increase in the availability and utilization of generic drug products in recent years, pharmacists are being faced with an ever-increasing array of
multisource products. Appropriate selection of a product from the plethora of
products on the market is not always an easy task; the quality of the drug product
must be considered, as well as the cost. The principles of biopharmaceutics indicate that the formulation and method of manufacture of a drug product can have a
marked effect on the bioavailability of the active ingredient. Thus, generic equivalents may not necessarily be therapeutically equivalent. Guidelines and criteria
have been established by the FDA to help judge whether one product can be substituted for another with assurance of equivalent therapeutic effect.
For pharmacists to provide informed product selection, it is essential that
they be knowledgeable about, and familiar with, these guidelines and criteria. This
requires an understanding of bioavailability, bioequivalence, and how they are
determined. The pharmacist can serve a major role in ensuring that only high quality products are dispensed, and in this way help reduce health care costs without
compromising quality of care.
Acknowledgment
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8.4.1
QUESTIONS
1.
b.
c.
relationship between the physical and chemical properties of a drug and its systemic
absorption.
d.
e.
2.
measurement of the rate and amount of drug that reaches the systemic circulation.
The bioavailability of various drug products can be evaluated by comparing their plasma concentration-time curves. The three most important parameters of comparison that can be
obtained directly from the curves are
a.
biologic half-life (t1/2), absorption rate constant, area under the curve (AUC).
b.
time of peak concentration (tmax), absorption rate constant, elimination rate constant.
c.
maximum drug concentration (Cmax), time of peak concentration (tmax), duration of action.
d.
area under the curve (AUC), time of peak concentration (tmax), maximum drug concentration
(Cmax).
e.
3.
b.
have equal areas under the curve after the administration of the same dose.
c.
have the same value for Cmax after administration of the same dose.
have equivalent rates and extents of absorption of the drug after administration of equal
doses.
d.
e.
4.
5.
If an oral capsule formulation of drug A produces a plasma concentration- time curve having
the same area under the curve (AUC) as that produced by an equivalent dose of drug A given
intravenously, it can generally be concluded that:
a.
b.
c.
d.
e.
5.Which of the following is NOT a criterion for therapeutic equivalence of two products,
according to the FDA?
a.
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6.
7.
8.
b.
c.
d.
e.
A test oral formulation has the same area under the plasma concentration- time curve as the reference formulation. This means that the two formulations
a.
b.
deliver the same total amount of drug to the body but are not necessarily bioequivalent.
c.
d.
deliver the same total amount of drug to the body and are, therefore, bioequivalent.
e.
In-vitro dissolution rate studies on drug products are useful in bioavailability evaluations only if
they can be correlated with
a.
b.
c.
d.
e.
b.
If we can be 90% certain that the mean values of AUC and Cmax for two products are within
80% to 125% of each other, then the two products are considered bioequivalent.
Bioequivalence studies are generally conducted in a panel of patients consisting of the target population for which the drug is intended.
c.
If two products are shown to be bioequivalent, we can always say with certainty that they
will be therapeutically equivalent.
e.
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9.
9.Which of the following statements about the FDA Orange Book is TRUE?
Drugs that are excluded from the Orange Book are not safe and effective and should not be
dispensed.
a.
b.
It contains therapeutic equivalence evaluations for all the drugs approved by the FDA.
c.
The Orange Book is an official compendium, and pharmacists can legally only dispense
those products listed as bioequivalent.
d.
The drug listings contain the names of only the companies that actually hold an approved
NDA or ANDA for a drug.
e.
10.
8.4.2
b.
c.
d.
e.
ANSWERS TO QUESTIONS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
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1.
AUMC iv
as discussed in chapter 4.
MRT iv = --------------------AUC iv
2.
1
k = --------------MRT iv
3.
ln 2
t 1 2 = -------k
4.
Cp 0iv = AUC k
5.
Dose iv
Vd = ---------------Cp 0iv
6.
Cp iv = Cp 0 e
7.
8.
AUMC po
- as discussed in chapter 4
MRT po = ---------------------AUC po
9.
10.
1
k a = -----------MAT
11.
kt
k
ln ----a-
k
t p = ---------------ka k
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12.
ka
kt
k t
Cp max = fD
------ ------------ (e p e a p )
V ka k
14.
15.
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8.6 Problems
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Caffeine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 8 - 1)
AHFS 00:00.00
GPI: 0000000000
Aramaki, S., et al., "Pharmacokinetics of caffeine and its metabolites in horses after intravenous, intramuscular, or oral administration", Chem Pharm Bull, Vol. 30, No. 11, (1991), p. 2999 - 3002.
This study deals with the pharmacokinetics of caffeine. Caffeine doses of 2.5 mg/kg were administered both intravenously and orally to horses with an average weight of about 500 kg. A summary of the some of data obtained from this
experiment is given below. Fill in the empty cells.
TABLE 8-24 Caffeine
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Dose (mg/kg)
2.5
2.5
2.5
2.5
ug
AUC -------- hr
mL
63.1
60.7
60
57
2
ug
AUMC -------- hr
mL
1442
1556.8
1600
1723
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug
Cp0 --------
mL
Vd (L)
ug
Cp at 1 hour --------
mL
f
ug-
Cpmax ------ mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
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Cefetamet Pivoxil
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 8 - 2)
AHFS 00:00.00
GPI: 0000000000
Ducharme, M., et. al., "Bioavailability of syrup and tablet formulations of cefetamet pivoxil", Antimicrobial Agents and Chemotherapy, Vol. 37, No. 12, (1993), p. 2706 - 2709.
Cefetamet pivoxil is a prodrug of cefetamet. This study compares the bioavailability of cefetamet pivoxil in tablet
form versus syrup form. A summary of the some of data obtained from this experiment is given below. Fill in the
approprate cells.
.
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Dose (mg)
250
500
500
500
ug
AUC -------- hr
mL
30.64
53.68
50
47
2
ug
AUMC -------- hr
mL
101.66
191.64
205.6
225.3
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug
Cp0 --------
mL
Vd (L)
ug
Cp at 1 hour --------
mL
f
ug-
Cpmax ------ mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
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Cefixime
(Problem 8 - 3)
AHFS 00:00.00
GPI: 0000000000
Faulkner, R. ,et al., "Absolute bioavailability of cefixime in man", Journal of Clinical Pharmacology, Vol. 28 (1988), p. 700 - 706.
Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram negative bacteria. In this study, sixteen subjects each received a 200 mg intravenous dose and then a 200 mg capsule with a
washout period between the administration of each dosage form. A summary of the some of data obtained from this
experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Brand Capsule
Generic Capsule
Dose (mg)
200
200
200
ug
AUC -------- hr
mL
47
23.6
20.2
2
ug
AUMC -------- hr
mL
183.3
162.8
187.5
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug
Cp0 --------
mL
Vd (L)
ug-
Cp at 1 hour ------ mL
f
ug
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
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Ceftibuten
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 8 - 4)
AHFS 00:00.00
GPI: 0000000000
Ceftibuten is a new oral cephalosporin with potent activity against enterobacteriaceae and certain gram positive organisms. In this study two groups received either a 400 mg oral dosage form of ceftibuten or a 200 mg iv bolus
dose of ceftibuten. A summary of the some of data obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Dose (mg)
200
400
400
400
ug
AUC -------- hr
mL
75.2
65.9
64.2
64
2
ug
AUMC -------- hr
mL
211.2
213.4
220
208
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug
Cp0 --------
mL
Vd (L)
ug
Cp at 1 hour --------
mL
f
ug
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
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Cimetidine
(Problem 8 - 5)
AHFS 00:00.00
GPI: 0000000000
Sandborn, W., et al., "Pharmacokinetics and pharmacodynamics of oral and intravenous cimetidine in seriously ill patients", Journal of Clinical Pharmacology, Vol. 30, (1990), p. 568 - 571.
Cimetidine is a histamine receptor antagonist which is used in the treatment of gastric and duodenal ulcer disease. In this study, patients received 300 mg of cimetidine as an iv bolus on the first day and data was collected. On
the second day, the patients received 300 mg orally and data was collected. A summary of the some of data obtained
from this experiment is given below.
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
300
300
300
ug
AUC -------- hr
mL
3.81
2.48
2.50
2
ug
AUMC -------- hr
mL
5.33
11.73
10.73
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug
Cp0 --------
mL
Vd (L)
ug
Cp at 1 hour --------
mL
f
ug
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-65
(Problem 8 - 6)
AHFS 00:00.00
GPI: 0000000000
Bauer, L., Gibaldi, M., and Vestal, R., "Influence of pharmacokinetic diurnal variation on bioavailability estimates", Clinical Pharmacokinetics, vol. 9, (1984), p. 184 - 187.
This article discusses the effects of diurnal variation on the bioavailability and clearance of theophylline. In
this study patients received a 500 mg dose every 12 hours either orally or by iv bolus. A summary of the some of data
obtained from this experiment for the time period between midnight and noon is given below.
From the preceding data, please calculate the following:
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Dose (mg)
500
500
500
500
ug
AUC -------- hr
mL
160.25
144.58
140
144
2
ug
AUMC -------- hr
mL
1821
1662
1785
1700
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug
Cp0 --------
mL
Vd (L)
ug
Cp at 1 hour --------
mL
f
ug
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-66
cis-5-Fluoro-1-[2-Hydroxymethyl-1,3-Oxathiolan-5-yl] Cytosine
(FTC)
(Problem 8 - 7)
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
AHFS 00:00.00
GPI: 0000000000
Frick, L. , et al., "Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-Fluoro-1-[2-Hydroxymethyl-1,3-Oxathiolan-5-yl] Cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus", Antimicrobial Agents and Chemotherapy, Vol. 37, No. 11, (1993), p. 2285 - 2292.
FTC is a 2',3'-didoexynucleoside analog that may be useful against HIV and HBV. In this study, rats with an
average weight of 270 g were given either iv or oral doses of 100 mg/kg. A summary of the some of data obtained
from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg/kg)
100
100
100
ug
AUC -------- hr
mL
265
168
175
2
ug
AUMC -------- hr
mL
19514
12600
13125
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug
Cp0 --------
mL
Vd (L)
ug
Cp at 1 hour --------
mL
f
ug-
Cpmax ------ mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-67
Hydromorphone
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 8 - 8)
AHFS 00:00.00
GPI: 0000000000
Vallner, J., et al., "Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to
human subjects", Journal of Clinical Pharmacology, Vol. 21, (1981), p. 152 - 156.
Hydromorphone hydrochloride is an analog of morphine which has about seven times the effect of morphine
when given intravenously. In this study, volunteers were given a 2 mg intravenous dose and a 4 mg oral dose of hydromorphone on separate days. A summary of the some of data obtained from this experiment is given below.
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
ug
AUC ------ hr
L
83
87.2
96
2
ug
AUMC ------ hr
L
289.4
401
432
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug
Cp0 ------
L
Vd (L)
ug
Cp at 1 hour ------
L
f
------
Cpmax ug
L
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-68
Isosorbide Dinitrate
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 8 - 9)
AHFS 00:00.00
GPI: 0000000000
Straehl, P. and Galeazzi, R., "Isosorbide dinitrate bioavailability , kinetics, and metabolism", Clinical Pharmacology and Therapeutics, Vol. 38m (1985), p. 140 - 149.
Isosorbide dinitrate is used in the treatment of angina pectoris, vasospastic angina, and congestive heart failure.
In this study volunteers received a 5 mg intravenous dose given over 5 minutes and a 10 mg tablet. The different dosage forms were separated by a washout period. A summary of the some of data obtained from this experiment is given
below.
From the preceding data, please calculate the following:
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg/kg)
10
10
AUC ug
------ hr
L
370.3
158
165
2
AUMC ug
------ hr
L
487
310
305
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug
Cp0 ------
L
Vd (L)
------
Cp at 1 hour ug
L
f
ug
Cpmax ------
L
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-69
Ketanserin
(Problem 8 - 10)
AHFS 00:00.00
GPI: 0000000000
Kurowski, M., "Bioavailability and pharmacokinetics of ketanserin in elderly subjects", Journal of Clinical Pharmacology, Vol. 28,
(1988), p. 700 - 706.
Ketanserin is a 5-hydroxytryptamine S2-antagonist. This study focuses on the kinetics of Ketanserin in the
elderly. Subjects were given either a 10 mg intravenous dose or a 40 mg oral tablet. A summary of the some of data
obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
10
40
40
ng
AUC -------- hr
mL
247
520
400
2
ng
AUMC -------- hr
mL
3991
8922
8922
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ng
Cp0 --------
mL
Vd (L)
ng
Cp at 1 hour --------
mL
f
ng
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-70
Methotrexate
(Problem 8 - 11)
AHFS 00:00.00
GPI: 0000000000
Seideman, P., et al., " The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis",
British Journal of Clinical Pharmacology, 35 (1993), p. 409 - 412.
The drug Methotrexate is a folic acid which has been shown to inhibit dihydrofolate reductase. The importance of this drug at present is mostly seen in the area of oncology, but lately it has been used for rheumatoid arthritis.
Methotrexate has a molecular weight of 454.4. In this study, the drug was administered both by IV bolus and orally as
a 15 mg dose. The following data was obtained:
From the preceding data, please calculate the following:
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
15
15
15
AUC nmole
---------------- hr
L
2752
2708
2700
2
AUMC nmole
---------------- hr
L
15887
18400
18500
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
nmole
Cp0 ----------------
L
Vd (L)
----------------
Cp at 1 hour nmole
L
f
nmole
Cpmax ----------------
L
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-71
Moclobemide
(Problem 8 - 12)
AHFS 00:00.00
GPI: 0000000000
Schoerlin, M. et al., "Disposition kinetics of moclobemide, a new MAO-A inhibitor, in subjects with impaired renal function", Journal of Clinical Pharmacology, Vol. 30 (1991), p. 272 - 284.
Moclobemide is an antidepressant agent that reversibly inhibits the A-isozyme of the monoamine oxidase
enzyme system. In this study, single IV and oral doses were administered to a patient. A summary of the some of data
obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
150
100
100
ug
AUC -------- hr
mL
2.58
1.70
1.52
2
ug
AUMC -------- hr
mL
6.35
5.91
5.90
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug
Cp0 --------
mL
Vd (L)
ug
Cp at 1 hour --------
mL
f
ug
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-72
Nalbuphine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 8 - 13)
AHFS 00:00.00
GPI: 0000000000
Nalbuphine hydrochloride is an agonist-antagonist opiod which is used for its analgesic actions. In this study,
volunteers were given single doses of four different nalbuphine forms. The data below focuses on a 10 mg iv dose and
a 45 mg dose of an oral solution. A summary of the some of data obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Dose (mg)
10
45
40
40
ng
AUC -------- hr
mL
86.9
70.3
62.5
60
2
ng
AUMC -------- hr
mL
288
306
280
270
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ng
Cp0 --------
mL
Vd (L)
ng
Cp at 1 hour --------
mL
f
ng
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-73
Nefazodone
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 8 - 14)
AHFS 00:00.00
GPI: 0000000000
Shukla, U. et al., "Pharmacokinetics, absolute bioavailability, and disposition of nefazodone in the dog", Drug Metabolism and
Disposition, Vol. 21, No. 3, (1993), p. 502 - 507.
Nefazodone was given to four healthy, adult, male beagles with an average weight of 11.0 kg. Each dog was
given a 10 mg/kg dose as a either a intravenous injection or as an oral solution or tablet. A summary of the some of
data obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Dose (mg/kg)
10
10
10
10
ng
AUC -------- hr
mL
6023
829
800
700
2
ng
AUMC -------- hr
mL
29283
4875
4800
4500
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ng
Cp0 --------
mL
Vd (L)
ng
Cp at 1 hour --------
mL
f
ng
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-74
Ondansetron
(Problem 8 - 15)
AHFS 00:00.00
GPI: 0000000000
Colthup, P., et al., "Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly", Journal of Pharmaceutical Sciences, Vol. 80, No. 9(1991), p. 868 - 871.
Ondansetron is a 5-hydroxyltryptamine compound which is useful in treating the nausea and vomiting which is
caused by the use of chemotherapy and radiation in the cancer patients. In order to determine the absolute bioavailability of oral Ondansetron, doses of 8 mg were given to two groups. One group received an oral dose and the other group
received an intravenous dose. A summary of the some of data obtained from this experiment is given below.
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
ng
AUC -------- hr
mL
246.5
139
145
2
ng
AUMC -------- hr
mL
1138
795
870
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ng
Cp0 --------
mL
Vd (L)
ng
Cp at 1 hour --------
mL
f
ng
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-75
Omeprazole
(Problem 8 - 16)
AHFS 00:00.00
GPI: 0000000000
Anderson, T., et al, "Pharmacokinetics of various single intravenous and oral doses of omeprazole", Eur Journal of Clinical Pharmacology, 39, (1990), p. 195 - 197.
Omeprazole (mw: 345.42) is an agent which inhibits gastric acid secretion from the parietal cell. It is useful in
treating such problems as ulcers and gastroesophageal reflux disease. One group received an iv bolus dose and the
other group received an oral dose. A summary of the some of data obtained from this experiment is given below.
Parameter
IV
Brand Capsule
Generic Capsule
Dose (mg)
20
40
40
mole
AUC ---------------- hr
L
3.2
3.5
3.0
2
mole
AUMC ---------------- hr
L
3.2
5.25
4.5
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
mole
Cp0 ----------------
L
Vd (L)
mole
Cp at 1 hour ----------------
f
mole
Cpmax ---------------
L
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-76
Paroxetine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 8 - 17)
AHFS 00:00.00
GPI: 0000000000
Lund, J., et al., "Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man", Journal
of Pharmacology and Toxicology, Vol. 51, (1982), p. 351 - 357.
Paroxetine kinetics and cardiovascular effects were studied in male subjects after single oral doses of 45 mg
and slow intravenous infusion of 23 - 28 mg. A summary of the some of data obtained from this experiment is given
below.
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
28
45
45
ng
AUC -------- hr
mL
467
750
675
2
ng
AUMC -------- hr
mL
6671
11250
10463
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ng
Cp0 --------
mL
Vd (L)
ng
Cp at 1 hour --------
mL
f
ng-
Cpmax ------ mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-77
Ranitidine
(Problem 8 - 18)
AHFS 00:00.00
GPI: 0000000000
Garg, D., et al., "Pharmacokinetics of ranitidine in patients with renal failure", Journal of Clinical Pharmacology, Vol. 26 (1986),
p. 286 - 291.
Ranitidine is an agent used in the treatment of peptic ulceration. In this study, ten patients with renal failure
received either a 50 mg intravenous bolus dose or a 150 mg tablet. A summary of the some of data obtained from this
experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
50
150
150
ng
AUC -------- hr
mL
5159
6422
6753
2
ng
AUMC -------- hr
mL
53415
78752
84413
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ng
Cp0 --------
mL
Vd (L)
ng
Cp at 1 hour --------
mL
f
ng
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-78
Sulpiride
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 8 - 19)
AHFS 00:00.00
GPI: 0000000000
Bressolle, F., Bres, J., and Faure-Jeantis, A., "Absolute bioavailability , rate of absorption, and dose proportionality of sulpiride in
humans", Journal of Pharmaceutical Sciences ,Vol. 81, No. 1 (1992), p. 26 - 32.
Sulpiride is a substituted benzamine antipsychotic. In this study, the drug was administered to two groups.
The first group received a 200 mg oral dose and the second group received a 100 mg intravenous infusion. A summary
of the some of data obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Dose (mg)
100
200
200
200
ug
AUC -------- hr
mL
8.27
8.79
8.6
8.0
2
ug
AUMC -------- hr
mL
79.1
87.3
91.1
84.5
Bioequivalence
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
ug
Cp0 --------
mL
Vd (L)
ug
Cp at 1 hour --------
mL
f
ug
Cpmax --------
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-79
8.7 Solutions
8.7.1
CAFFEINE ON PAGE 61
Aramaki, S., et al., "Pharmacokinetics of caffeine and its metabolites in horses after intravenous, intramuscular, or oral administration", Chem Pharm Bull, Vol. 30, No. 11, (1991), p. 2999 - 3002.
This study deals with the pharmacokinetics of caffeine. Caffeine doses of 2.5 mg/kg were administered both intravenously and orally to horses with an average weight of about 500 kg. A summary of the some of data obtained from this
experiment is given below. Fill in the empty cells.
TABLE 8-25 Caffeine
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Dose (mg/kg)
2.5
2.5
2.5
2.5
ug
AUC -------- hr
mL
63.1
60.7
60
57
2
ug
AUMC -------- hr
mL
1442
1556.8
1600
1723
MRT (hr)
22.9
25.7
26.7
30.2
2.79
3.81
7.36
0.358
0.262
0.136
0.78
0.59
0.31
0.96
0.95
.90
1.98
1.83
1.45
0.79
6.69
8.19
12.1
1.5
MAT (hr)
ke (hr-1)
0.0438
ka (hr-1)
ug
Cp0 --------
mL
2.76
V d (L/kg)
0.91
ug-
Cp at 1 hour ------ mL
2.64
f
ug
Cpmax --------
mL
Bioequivalence
2.76
Tmax (hr)
Relative Bioavailability
0.95
NO
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-80
h
1442ug
--------------mL
---------------------------- = 22.9
2
h
63.1ug
--------------mL
1.
MRT = AUMC
------------------ =
AUC
2.
1 = ------------1 = 0.044 h 1
k = -----------MRT 22.9h
3.
ln 2 = 0.693
t 1 2 = ---------------------------- = 15.75h
1
k
0.044h
4.
1
h
ugCp 0 = AUC k = 63.1 ug
------------ 0.0044h
= 2.76 ------mL
mL
5.
hours
Dose = 2.5 mg
------- 500kg = 1250mg
kg
ug- = 2.78 mg
Cp 0 = 2.78 ------------mL
L
1250mg- = 449.6L = ------------------------2.5mg kg = 0.91 ----LVd = Dose
------------- = ------------------Cp 0
mg
mg
kg
2.78 ------2.78------L
L
6.
7.
Cp = Cp0 e
kt
h
2.5 mg
------60 ug
------------AUC oral Dose iv
mL
kg = 0.95
f = --------------------- ----------------- = -------------------- -----------------------Dose oral AUC iv
h
2.5 mg
------- 63.1ug
------------kg
mL
2
8.
MRT po
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-81
10.
1 = --------1 - = 0.358hr 1
k a = -----------MAT
2.79
0.358hr
k a
ln -----------------------
1
ln -----
0.044h
k
tp = ---------------- = ------------------------------------------------------ = 6.7hr
1
1
ka k
0.358hr 0.044hr
1
11.
12.
13.
ktp
katp
( 0.044 6.7 )
( 0.358 6.7 )
fD
ka
0.96 1250mg
0.358hr
e
) = ----------------------------------- ------------------------------------------------- ( e
Cp max = ------ -------------- ( e
e
)
1
V ka k
449L
( 0.358 0.044 ) hr
( AUC
) ( Dose
generic
generic
Relative Bioavailability (R.B. or C.B.) = ---------------------------------------------------------------------
ug-
57 ------ mL
hr 2.5 mg
-------
km
CB = ------------------------------------------------------------- = 0.95
ug- hr 2.5 mg
60 -------------
mL
km
14.
t p generic
-------------= 12.1hr
---------------- = 1.5 = NO
8.19hr
t pbrand
C p max g eneric
0.80 < ----------------------- < 1.25
C p max b rand
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-82
8.7.2
Ducharme, M., et. al., "Bioavailability of syrup and tablet formulations of cefetamet pivoxil", Antimicrobial Agents and Chemotherapy, Vol. 37, No. 12, (1993), p. 2706 - 2709.
Cefetamet pivoxil is a prodrug of cefetamet. This study compares the bioavailability of cefetamet pivoxil in tablet
form versus syrup form. A summary of the some of data obtained from this experiment is given below. Fill in the
approprate cells.
.
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Dose (mg)
250
500
500
500
ug- hr
AUC ------ mL
30.64
53.68
50
47
ug- hr 2
AUMC ------ mL
101.66
191.64
205.6
225.3
MRT (hr)
3.32
3.57
4.11
4,79
0.252
0.794
1.48
3.97
1.26
0.678
12.62
9.03
5.91
0.88
0.82
0.77
13.1
9.6
7.4
0.77
0.70
1.49
2.15
1.44
MAT (hr)
ke
(hr-1)
0.301
ka (hr-1)
ug
Cp0 --------
mL
9.23
Vd (L)
27.1
ug-
Cp at 1 hour ------ mL
6.83
f
ug
Cpmax --------
mL
Bioequivalence
9.23
Tmax (hr)
Relative Bioavailability
0.94
NO
2
1.
mg h
101.66 ----------------L
MRT = AUMC
------------------ = ---------------------------------= 3.32 hours
2
AUC
mg
h
30.64 ----------------L
Where AUMC is that which is given for the intravenous dose.
Where AUC is that which is given for the intravenous dose.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-83
2.
1
1
1
k = -----------= ------------- = 0.301 h
MRT 3.32h
3.
ln 2 = --------------------0.693 = 2.3h
t 1 2 = -------1
k
0.301h
4.
1
h
Cp 0 = AUC k = 30.64 mg
-------------- 0.301h = 9.22 mg
------L
L
5.
6.
7.
250mg
V d = Dose
------------- = ------------------ = 27.06L
Cp 0
9.24mg
------L
Cp = Cp 0 e
kt
0.301 ( 1 )
mg
= 9.24 mg
------- ( e
) = 6.84------L
L
h
53.68mg
-------------AUC oral Dose iv
L
250mg - = 0.876
f = --------------------- ----------------- = ----------------------------- ---------------------------Dose oral AUC iv
500mg
h
30.64 mg
-------------L
2
8.
MRT po
mg h
191.64 ----------------L
= AUMC
------------------ = ---------------------------------= 3.57h
AUC
mg
h
53.68 --------------L
k a
ln --------------------
ln -----
0.301h 1
k
t p = ---------------- = ------------------------------------------- = 0.7h
1
1
ka k
4.0h 0.301h
1
11.
12.
13.
0.301 ( 0.7 )
3.97 ( 0.7 )
ka ( e kt e k a t ) = 0.88
( 500mg )
3.97hr
mg
Cp max = fD
------ -------------------------------------------- ---------------------------------------------- ( e
e
) = 13.1------1
V ka k
27.1L
L
( 3.97 0.301 ) hr
( AUC
) ( Dose
generic
generic
Relative Bioavailability (R.B. or C.B.) = ---------------------------------------------------------------------
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-84
ug-
47 ------ mL
hr 500mg
CB = -------------------------------------------------------- = 0.94
ug- hr 500mg
50 ------ mL
14.
t p generic
-------------= 2.15hr
---------------- = 1.44 = NO
1.49hr
t pbrand
C p max g eneric
0.80 < ----------------------- < 1.25
C p max b rand
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-85
8.7.3
CEFIXIME ON PAGE 63
Faulkner, R. ,et al., "Absolute bioavailability of cefixime in man", Journal of Clinical Pharmacology, Vol. 28 (1988), p. 700 - 706.
Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram negative bacteria. In this study, sixteen subjects each received a 200 mg intravenous dose and then a 200 mg capsule with a
washout period between the administration of each dosage form. A summary of the some of data obtained from this
experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Brand Capsule
Generic Capsule
Dose (mg)
200
200
200
ug
AUC -------- hr
mL
47
23.6
20.2
2
ug
AUMC -------- hr
mL
183.3
162.8
187.5
MRT (hr)
3.9
6.9
9.3
3.0
5.38
0.334
0.186
1.5
0.77
0.50
0.43
2.5
1.6
0.64
3.4
4.6
1.33
MAT (hr)
ke
(hr-1)
0.256
ka (hr-1)
ug
Cp0 --------
mL
12.1
Vd (L)
16.6
ug
Cp at 1 hour --------
mL
9.3
f
ug-
Cpmax ------ mL
Bioequivalence
12.1
Tmax (hr)
Relative Bioavailability
0.86
NO
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-86
8.7.4
CEFTIBUTEN ON PAGE 64
Ceftibuten is a new oral cephalosporin with potent activity against enterobacteriaceae and certain gram positive organisms. In this study two groups received either a 400 mg oral dosage form of ceftibuten or a 200 mg iv bolus
dose of ceftibuten. A summary of the some of data obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Dose (mg)
200
400
400
400
ug- hr
AUC ------ mL
75.2
65.9
64.2
64
ug- hr 2
AUMC ------ mL
211.2
213.4
220
208
MRT (hr)
2.94
MAT (hr)
ke (hr-1)
3.24
3.43
3.25
0.297
0.485
0.309
3.37
2.06
3.24
16.9
15.3
16.4
0.44
0.42
0.43
17.3
15.3
16.7
1.09
0.76
1.05
0.78
0.74
0.390
ka (hr-1)
ug-
Cp0 ------ mL
25.6
Vd (L)
7.8
ug
Cp at 1 hour --------
mL
18.2
f
ug
Cpmax --------
mL
Bioequivalence
25.6
Tmax (hr)
Relative Bioavailability
NO
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-87
8.7.5
CIMETIDINE ON PAGE 65
Sandborn, W., et al., "Pharmacokinetics and pharmacodynamics of oral and intravenous cimetidine in seriously ill patients", Journal of Clinical Pharmacology, Vol. 30, (1990), p. 568 - 571.
Cimetidine is a histamine receptor antagonist which is used in the treatment of gastric and duodenal ulcer disease. In this study, patients received 300 mg of cimetidine as an iv bolus on the first day and data was collected. On
the second day, the patients received 300 mg orally and data was collected. A summary of the some of data obtained
from this experiment is given below.
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
300
300
300
ug- hr
AUC ------ mL
3.81
2.48
2.50
ug- hr 2
AUMC ------ mL
5.33
11.73
10.73
MRT (hr)
1.40
4.73
4.29
3.33
2.89
0.300
0.346
0.32
0.37
0.65
0.66
0.40
0.44
1.1
2.1
2.0
0.94
MAT (hr)
ke
(hr-1)
0.715
ka (hr-1)
ug-
Cp0 ------ mL
2.72
Vd (L)
110
ug
Cp at 1 hour --------
mL
1.33
f
ug
Cpmax --------
mL
Bioequivalence
2.72
Tmax (hr)
Relative Bioavailability
YES
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-88
8.7.6
Bauer, L., Gibaldi, M., and Vestal, R., "Influence of pharmacokinetic diurnal variation on bioavailability estimates", Clinical Pharmacokinetics, vol. 9, (1984), p. 184 - 187.
This article discusses the effects of diurnal variation on the bioavailability and clearance of theophylline. In
this study patients received a 500 mg dose every 12 hours either orally or by iv bolus. A summary of the some of data
obtained from this experiment for the time period between midnight and noon is given below.
From the preceding data, please calculate the following:
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Dose (mg)
500
500
500
500
ug- hr
AUC ------ mL
160.25
144.58
140
144
ug- hr 2
AUMC ------ mL
1821
1662
1785
1700
MRT (hr)
11.40
11.50
12.75
11.8
0.13
1.39
0.44
7.58
0.721
2.26
11.8
6.02
10.7
0.90
0.87
0.90
12.1
9.20
11.1
1.21
.059
3.3
1.5
0.45
MAT (hr)
ke
(hr-1)
0.088
ka (hr-1)
ug-
Cp0 ------ mL
14.1
Vd (L)
35.5
ug
Cp at 1 hour --------
mL
12.9
f
ug
Cpmax --------
mL
Bioequivalence
14.1
Tmax (hr)
Relative Bioavailability
1.03
NO
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-89
8.7.7
CIS-5-FLUORO-1-[2-HYDROXYMETHYL-1,3-OXATHIOLAN-5-YL]
CYTOSINE (FTC) ON PAGE 67
Frick, L. , et al., "Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-Fluoro-1-[2-Hydroxymethyl-1,3-Oxathiolan-5-yl] Cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus", Antimicrobial Agents and Chemotherapy, Vol. 37, No. 11, (1993), p. 2285 - 2292.
FTC is a 2',3'-didoexynucleoside analog that may be useful against HIV and HBV. In this study, rats with an
average weight of 270 g were given either iv or oral doses of 100 mg/kg. A summary of the some of data obtained
from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg/kg)
100
100
100
ug- hr
AUC ------ mL
265
168
175
ug- hr 2
AUMC ------ mL
19514
12600
13125
MRT (hr)
73.6
75
75
1.36
1.36
0.734
0.734
1.18
1.23
0.63
0.66
2.1
2.2
1.04
5.54
5.54
1.0
MAT (hr)
ke
(hr-1)
.0136
ka (hr-1)
ug-
Cp0 ------ mL
3.6
Vd (L/kg)
27.7
ug
Cp at 1 hour --------
mL
3.55
f
ug
Cpmax --------
mL
Bioequivalence
3.6
Tmax (hr)
Relative Bioavailability
1.04
YES
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-90
8.7.8
HYDROMORPHONE ON PAGE 68
Vallner, J., et al., "Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to
human subjects", Journal of Clinical Pharmacology, Vol. 21, (1981), p. 152 - 156.
Hydromorphone hydrochloride is an analog of morphine which has about seven times the effect of morphine
when given intravenously. In this study, volunteers were given a 2 mg intravenous dose and a 4 mg oral dose of hydromorphone on separate days. A summary of the some of data obtained from this experiment is given below.
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
83
87.2
96
289.4
401
432
3.49
4.60
4.50
1.11
1.03
0.899
0.987
12.6
14.7
0.53
0.56
14.6
16.6
1.13
1.87
1.77
0.95
ug
AUC ------ hr
L
2
------ hr
AUMC ug
L
MRT (hr)
MAT (hr)
ke
(hr-1)
0.287
ka (hr-1)
ug
Cp0 ------
L
23.8
Vd (L)
84
------
Cp at 1 hour ug
L
17.9
f
ug
Cpmax ------
L
Bioequivalence
23.8
Tmax (hr)
Relative Bioavailability
1.1
YES
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-91
8.7.9
Straehl, P. and Galeazzi, R., "Isosorbide dinitrate bioavailability , kinetics, and metabolism", Clinical Pharmacology and Therapeutics, Vol. 38m (1985), p. 140 - 149.
Isosorbide dinitrate is used in the treatment of angina pectoris, vasospastic angina, and congestive heart failure.
In this study volunteers received a 5 mg intravenous dose and a 10 mg tablet. The different dosage forms were separated by a washout period. A summary of the some of data obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg/kg)
10
10
370.3
158
165
487
310
305
1.32
1.96
1.85
0.65
0.53
1.546
1.875
60.1
66.2
0.21
0.22
60.4
67.8
1.12
0.90
0.81
0.90
ug
AUC ------ hr
L
2
ug
AUMC ------ hr
L
MRT (hr)
MAT (hr)
ke (hr-1)
0.760
ka (hr-1)
------
Cp0 ug
L
282
Vd (L)
17.75
ug
Cp at 1 hour ------
L
132
f
ug
Cpmax ------
L
Bioequivalence
282
Tmax (hr)
Relative Bioavailability
1.04
YES
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-92
8.7.10
KETANSERIN ON PAGE 70
Kurowski, M., "Bioavailability and pharmacokinetics of ketanserin in elderly subjects", Journal of Clinical Pharmacology, Vol. 28,
(1988), p. 700 - 706.
Ketanserin is a 5-hydroxytryptamine S2-antagonist. This study focuses on the kinetics of Ketanserin in the
elderly. Subjects were given either a 10 mg intravenous dose or a 40 mg oral tablet. A summary of the some of data
obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
10
40
40
ng- hr
AUC ------ mL
541
112.5
103.9
ng- hr 2
AUMC ------ mL
11700
24900
22900
MRT (hr)
21.6
22.1
22.0
0.5
0.4
2.0
2.5
43.6
42.7
.052
0.48
47.6
44.5
0.94
1.93
1.63
0.84
MAT (hr)
ke (hr-1)
Bioequivalence
0.0402
ka (hr-1)
ng-
Cp0 ------ mL
25.0
Vd (L)
400
ng
Cp at 1 hour --------
mL
23.9
f
ng
Cpmax --------
mL
25.0
Tmax (hr)
Relative Bioavailability
0.92
YES
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-93
8.7.11
METHOTREXATE ON PAGE 71
Seideman, P., et al., " The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis",
British Journal of Clinical Pharmacology, 35 (1993), p. 409 - 412.
The drug Methotrexate is a folic acid which has been shown to inhibit dihydrofolate reductase. The importance of this drug at present is mostly seen in the area of oncology, but lately it has been used for rheumatoid arthritis.
Methotrexate has a molecular weight of 454.4. In this study, the drug was administered both by IV bolus and orally as
a 15 mg dose. The following data was obtained:
From the preceding data, please calculate the following:
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
15
15
15
nmole
AUC ---------------- hr
2752
2708
2700
2
nmole
AUMC ---------------- hr
L
15887
18400
18500
MRT (hr)
5.77
6.79
6.85
1.02
1.08
0.979
0.927
265
256
0.98
0.98
323
318
0.98
2.15
2.23
1.04
MAT (hr)
ke
(hr-1)
0.173
ka (hr-1)
nmole
Cp0 ----------------
L
477
Vd (L)
69.3
nmole
Cp at 1 hour ----------------
401
f
----------------
Cpmax nmole
Bioequivalence
477
Tmax (hr)
Relative Bioavailability
1.0
YES
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-94
8.7.12
MOCLOBEMIDE ON PAGE 72
Schoerlin, M. et al., "Disposition kinetics of moclobemide, a new MAO-A inhibitor, in subjects with impaired renal function", Journal of Clinical Pharmacology, Vol. 30 (1991), p. 272 - 284.
Moclobemide is an antidepressant agent that reversibly inhibits the A-isozyme of the monoamine oxidase
enzyme system. In this study, single IV and oral doses were administered to a patient. A summary of the some of data
obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
150
100
100
ug- hr
AUC ------ mL
2.58
1.70
1.52
ug- hr 2
AUMC ------ mL
6.35
5.91
5.90
MRT (hr)
2.46
3.48
3.80
1.02
1.42
0.985
0.704
0.344
0.250
.099
.088
.037
0.29
.079
1.53
1.85
1.21
MAT (hr)
ke (hr-1)
0.406
ka (hr-1)
ug-
Cp0 ------ mL
1.05
Vd (L)
143
ug
Cp at 1 hour --------
mL
0.698
f
ug
Cpmax --------
mL
Bioequivalence
1.05
Tmax (hr)
Relative Bioavailability
0.89
NO
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-95
8.7.13
NALBUPHINE ON PAGE 73
Nalbuphine hydrochloride is an agonist-antagonist opiod which is used for its analgesic actions. In this study,
volunteers were given single doses of four different nalbuphine forms. The data below focuses on a 10 mg iv dose and
a 45 mg dose of an oral solution. A summary of the some of data obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Dose (mg)
10
45
40
40
ng- hr
AUC ------ mL
86.9
70.3
62.5
60
ng- hr 2
AUMC ------ mL
288
306
280
270
MRT (hr)
3.31
4.35
4.48
4.5
1.04
1.17
1.19
0.963
0.858
0.843
11.1
9.2
8.7
0.180
0.180
0.173
12.5
10.7
10.2
0.95
1.76
1.88
1.90
1.01
MAT (hr)
ke (hr-1)
.0301
ka (hr-1)
ng-
Cp0 ------ mL
26.2
Vd (L)
381
ng
Cp at 1 hour --------
mL
19.4
f
ng
Cpmax --------
mL
Bioequivalence
26.2
Tmax (hr)
Relative Bioavailability
0.96
YES
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-96
8.7.14
NEFAZODONE ON PAGE 74
Shukla, U. et al., "Pharmacokinetics, absolute bioavailability, and disposition of nefazodone in the dog", Drug Metabolism and
Disposition, Vol. 21, No. 3, (1993), p. 502 - 507.
Nefazodone was given to four healthy, adult, male beagles with an average weight of 11.0 kg. Each dog was
given a 10 mg/kg dose as a either a intravenous injection or as an oral solution or tablet. A summary of the some of
data obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Dose (mg/kg)
10
10
10
10
ng- hr
AUC ------ mL
6023
829
800
700
ng- hr 2
AUMC ------ mL
29283
4875
4800
4500
MRT (hr)
4.86
5.88
6.0
6.43
1.02
1.14
1.57
0.982
0.879
0.638
94.8
85.7
60.7
0.138
0.133
0.116
112.7
105.6
84.0
0.80
2.0
2.16
2.62
1.21
MAT (hr)
ke (hr-1)
0.210
ka (hr-1)
ng-
Cp0 ------ mL
1238
Vd (L)
8.07
ng
Cp at 1 hour --------
mL
1009
f
ng
Cpmax --------
mL
Bioequivalence
1238
Tmax (hr)
Relative Bioavailability
0.88
YES
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-97
8.7.15
ONDANSETRON ON PAGE 75
Colthup, P., et al., "Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly", Journal of Pharmaceutical Sciences, Vol. 80, No. 9(1991), p. 868 - 871.
Ondansetron is a 5-hydroxyltryptamine compound which is useful in treating the nausea and vomiting which is
caused by the use of chemotherapy and radiation in the cancer patients. In order to determine the absolute bioavailability of oral Ondansetron, doses of 8 mg were given to two groups. One group received an oral dose and the other group
received an intravenous dose. A summary of the some of data obtained from this experiment is given below.
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
ng- hr
AUC ------ mL
246.5
139
145
ng- hr 2
AUMC ------ mL
1138
795
870
MRT (hr)
4.62
5.72
6.0
1.10
1.38
0.907
0.723
15.9
14.7
0.56
0.59
19.2
18.8
2.1
2.4
MAT (hr)
ke
(hr-1)
0.217
ka (hr-1)
ng-
Cp0 ------ mL
53.4
Vd (L)
150
ng
Cp at 1 hour --------
mL
43
f
ng
Cpmax --------
mL
Bioequivalence
53.4
Tmax (hr)
1.1
Relative Bioavailability
1.04
YES
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-98
8.7.16
OMEPRAZOLE ON PAGE 76
Anderson, T., et al, "Pharmacokinetics of various single intravenous and oral doses of omeprazole", Eur Journal of Clinical Pharmacology, 39, (1990), p. 195 - 197.
Omeprazole (mw: 345.42) is an agent which inhibits gastric acid secretion from the parietal cell. It is useful in
treating such problems as ulcers and gastroesophageal reflux disease. One group received an iv bolus dose and the
other group received an oral dose. A summary of the some of data obtained from this experiment is given below.
Parameter
IV
Brand Capsule
Generic Capsule
Dose (mg)
20
40
40
mole hr
AUC ---------------
3.2
3.5
3.0
2
mole
hr
AUMC ---------------
3.2
5.25
4.5
MRT (hr)
1.0
1.5
1.5
0.5
0.5
1.63
1.40
0.55
0.47
1.8
1.5
0.86
0.69
0.69
MAT (hr)
ke
(hr-1)
ka (hr-1)
mole
Cp0 ----------------
3.2
Vd (L)
52.4
mole
Cp at 1 hour ---------------
L
1.18
f
mole
Cpmax ----------------
Bioequivalence
3.2
Tmax (hr)
Relative Bioavailability
0.86
YES
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-99
8.7.17
PAROXETINE ON PAGE 77
Lund, J., et al., "Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man", Journal
of Pharmacology and Toxicology, Vol. 51, (1982), p. 351 - 357.
Paroxetine kinetics and cardiovascular effects were studied in male subjects after single oral doses of 45 mg
and slow intravenous infusion of 28 mg. A summary of the some of data obtained from this experiment is given below.
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
28
45
45
ng
AUC -------- hr
mL
467
750
675
2
ng
AUMC -------- hr
mL
6671
11250
10463
MRT (hr)
14.3
MAT (hr)
ke (hr-1)
15
15.5
0.72
1.22
1.40
.082
37.9
25.5
0.90
44.8
37.6
0.84
2.25
3.27
1.45
0.07
ka (hr-1)
ng
Cp0 --------
mL
32.7
Vd (L)
856
ng-
Cp at 1 hour ------ mL
30.5
f
ng
Cpmax --------
mL
Bioequivalence
32.7
Tmax (hr)
Relative Bioavailability
0.90
NO
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
8-100
8.7.18
RANITIDINE ON PAGE 78
Garg, D., et al., "Pharmacokinetics of ranitidine in patients with renal failure", Journal of Clinical Pharmacology, Vol. 26 (1986),
p. 286 - 291.
Ranitidine is an agent used in the treatment of peptic ulceration. In this study, ten patients with renal failure
received either a 50 mg intravenous bolus dose or a 150 mg tablet. A summary of the some of data obtained from this
experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Brand Tablet
Generic Tablet
Dose (mg)
50
150
150
ng- hr
AUC ------ mL
5159
6422
6753
ng- hr 2
AUMC ------ mL
53415
78752
84413
MRT (hr)
10.4
12.3
12.5
1.91
2.15
0.524
0.466
240
231
.0415
0.436
423
432
1.02
3.96
4.26
1.07
MAT (hr)
ke (hr-1)
Bioequivalence
0.0966
ka (hr-1)
ng-
Cp0 ------ mL
498
Vd (L)
100
ng
Cp at 1 hour --------
mL
452
f
ng
Cpmax --------
mL
498
Tmax (hr)
Relative Bioavailability
1.05
YES
Basic Pharmacokinetics
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8-101
8.7.19
SULPIRIDE ON PAGE 79
Bressolle, F., Bres, J., and Faure-Jeantis, A., "Absolute bioavailability , rate of absorption, and dose proportionality of sulpiride in
humans", Journal of Pharmaceutical Sciences ,Vol. 81, No. 1 (1992), p. 26 - 32.
Sulpiride is a substituted benzamine antipsychotic. In this study, the drug was administered to two groups.
The first group received a 200 mg oral dose and the second group received a 100 mg intravenous infusion. A summary
of the some of data obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter
IV
Oral Solution
Brand Tablet
Generic Tablet
Dose (mg)
100
200
200
200
ug- hr
AUC ------ mL
8.27
8.79
8.6
8.0
ug- hr 2
AUMC ------ mL
79.1
87.3
91.1
84.5
MRT (hr)
9.56
MAT (hr)
ke (hr-1)
9.93
10.6
10.6
0.367
1.02
1.0
2.72
0.972
1.0
0.798
0.526
0.498
0.53
0.52
0.48
0.807
0.687
0.643
0.94
1.24
2.57
2.52
0.98
0.865
ka (hr-1)
ug-
Cp0 ------ mL
0.865
Vd (L)
116
ug
Cp at 1 hour --------
mL
0.779
f
ug
Cpmax --------
mL
Bioequivalence
0.865
Tmax (hr)
Relative Bioavailability
0.93
YES
Basic Pharmacokinetics
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8-102
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166.
Feinberg, J.L., A Pharmacist's Survival Guide to the Generic Drug Scandal, Consult. Pharm., 5(1):15-23,
1990.
167.
Foster, T.S., Selecting Therapeutically Equivalent Products: Special Cases, Am. Pharm., NS31(11):49-54,
1991.
168.
Ross, M.B., Status of Generic Substitution: Problematic Drug Classes Reviewed, Hosp. Formul., 24:441-449,
1989.
169.
Sanderson, J.H. and Lewis, J.A., Differences in Side-Effect Incidence in Patients on Proprietary and Generic
Propranolol, The Lancet, Apr. 26:967- 968, 1986.
170.
Ansbacher, R., Conjugated Estrogens: Do Not Substitute, Am. Pharm., NS30(7):27-28, 1990.
171.
Locniskar, A., Greenblatt, D.J., Harmatz, J.S., and Shader, R.I., Bioinequivalence of a Generic Brand of Diazepam, Biopharm. Drug Disp., 10:597-605, 1989.
172.
Rentmeester, T.W., Doelman, J.C., and Hulsman, J.A.R.J., Carbamazepine: Merkpreparaat en Generiek,
Pharm. Weekbl., 125(43):1108-1110, 1990.
173.
Welty, T.E., Pickering, P.R., Hale, B.C. and Arazi, R., Loss of Seizure Control With Generic Substitution of
Carbamazepine, Annals Pharmacotherapy, 26:775-776, 1992.
174.
Grubb, B.P., Recurrence of Ventricular Tachycardia After Conversion From Proprietary to Generic Procainamide, Am. J. Cardiol., 63:1532-1533, 1989.
175.
Cunha, B.A., Nitrofurantoin - Bioavailability and Therapeutic Equivalence, Adv. Therapy, 5(3):54-63, 1988.
176.
177.
Check, W.A., Caution Urged in Prescribing of Generic Antiarrhythmic Drugs, Consult. Pharm.,
5(11):718-721, 1990.
178.
Fincham, J.E., Therapeutic Failure with Generic Hydrochlorothiazide- Triamterene in an Elderly Female: A
Case Report, J. Ger. Drug Therapy, 5(4):85-89, 1991.
179.
Fincham, J.E., Therapeutic Failure with Generic Clonidine in An Elderly Female: A Case Report, J. Ger. Drug
Therapy, 3(1):83-87, 1988.
180.
Ansbacher, R., Bioequivalence of Conjugated Estrogen Products, Clin. Pharmacokinet., 24(4):271-274, 1993.
Basic Pharmacokinetics
REV. 99.4.25
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8-111
CHAPTER 9
Clearance
OBJECTIVES
1.
Given patient information regarding organ function, the student will calculate (III)
changes in clearance and other pharmacokinetic parameters inherent in compromised patients.
2.
3.
Determine clearance of an organ based on dose, AUC, and fraction of drug eliminated by the organ
4.
5.
6.
Prepare a professional consult (V) and justify (VI) modifications in drug therapy
based on clearance of a drug.
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9-1
Clearance
9.1 Equations
Rate of Elimination
Cl = --------------------------------------------------Serum Concentration
(EQ 9-1)
D os
Cl tot = f--------------AUC
(EQ 9-2)
(EQ 9-3)
(EQ 9-4)
L
min
L
Q r = 0.0191 -------------------- renal blood perfusion 70kg 60 --------- 80 -----blood
min kg
hr
hr
(EQ 9-5)
L
min
L
Q H = 0.0238 -------------------- hepatic blood perfusion 70kg 60 --------- 100 -----blood
min kg
hr
hr
(EQ 9-6)
Er = ( Cl r ) Q r
(EQ 9-7)
E H = ( Cl H ) Q H
(EQ 9-8)
Q Cl
f u Cl int = ---------------Q Cl
(EQ 9-9)
Cl int
Q Cl--------------Q
Cl
= ---------------fu
(EQ 9-10)
f u Cl int
F i = ------------------------f u Cl int
(EQ 9-11)
FR = Q
------Q
(EQ 9-12)
Fi FR
F Cl = ----------------------------------------F R + Er ( Fi FR )
(EQ 9-13)
H + Cl r
Cl tot
k V = Cl
FCl tot = ------------- = -------------------------------------------Cl tot
k V
Cl H + Cl r
(EQ 9-14)
(EQ 9-15)
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9-2
Clearance
L T
Metabolic Clearance: Removal process is metabolism. Fluid is usually blood (rarely plasma or serum).
( Cl m )
( Cl H )
Cl m
organ.
Creatinine Clearance: This is Cl r applied to endogenous creatinine.
It is used to monitor renal function, and thus is a valuable parameter for calculating
dosage regimens in elderly patients or those suffering from renal dysfunction. Creatinine t 1 2 = 231min
( Cl cr )
Cl r
filtration rate.
Value for normal males: 124.5 9.7 ml/min
Value for normal females: 108.8 13.5 ml/min
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Clearance
(EQ 9-16)
Xu
a = -------------( C s ) cr
(EQ 9-17)
Thus,
The volume of serum from which this creatinine is removed in unit time is
this is the definition of clearance. Hence,
( Xu t )
a = -------------------------T
Cl cr = ----t
( C s ) cr
a t ;
(EQ 9-18)
min
ml
Cl cr = 104.2 --------min
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9-4
Clearance
9.4.1
RENAL CLEARANCE
The plasma renal clearance of a drug may be measured analogously to creatinine
clearance:
( Xu t )
Cl r = --------------------------TCp
(EQ 9-19)
= k u X = k u VC p
(EQ 9-20)
(EQ 9-21)
Cp ?
Note that if Cl r > 117 20ml min (males), it may indicate active secretion of the drug
into the kidney tubules. If Cl r < 108 20ml min (females), it may indicate reabsorption of the drug from the kidney tubules.
9.4.2
By analogy,
0.693V
Cl tot = KV = ----------------t1 2
and
K = ku + km
, so
Cl tot = Cl r + Cl m
(EQ 9-22)
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Clearance
F Cl
tot
Cl h + Cl r
K V
= ------------------------ = ---------------KV
Cl h + Cl r
(EQ 9-23)
where X is new or altered variable. Hepatic function and renal function are not a
priori connected, although some physiological functional changes might result in
similar changes in clearance of both organs. We can see from equation 9-12 that
changes in total body clearance can result in changes in either K, V, or both. The
consequences of that will be discussed in the section on dosage regimens.
9.4.3
( Cp )
ss
Q= ----Cl
f( Xa)
fD
fD
Cl = ---------------0 = --------------- = -----------
AUC
C p dt C p dt
0
fD = ----------- Cl
These examples are all model-independent expressions, which are very useful in
calculating dosage regimens. The importance of clearance terms rests on their ability to account for variations in both t 1 2 and / or V simultaneously, as both these
parameters can change in disease states and with age.
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Clearance
QH f u ( Cl H ) int
Cl H = -----------------------------------------Q H + f u ( Cl H ) int
(EQ 9-24)
Where Q H is the rate of blood flow through the liver (assumed 23.8 ml/min/Kg
body weight in normal adult),
fu is the fraction unbound of the drug, and
( Cl H )
int
If there were no physiological limits to the rate of blood flow( Q H ), hence equation 9-24 becomes
Cl H = ( Cl H ) int
(EQ 9-25)
This equation provides a definition for intrinsic clearance, namely the clearance of
a drug were there to be no physiological limits on the rate of blood flow through
the clearing organ.
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9-7
Clearance
(EQ 9-26)
Where Q r is the rate of blood flow through the kidney (assumed 19.1 ml/min per
Kg body weight in normal adults), and
( Cl r )
int
Note that the value of Cl cr (assumed 1.75 ml.min per Kg body weight in normal
adults) is about 9% of Q r .
9.5.2
Cl
E H = --------HQH
Where
EH
(EQ 9-27)
(EQ 9-28)
Thus, the range of values of E H is from zero, when ( Cl H ) int = 0 , to one, when
Q H = 0 or ( Cl H ) int Q H . For example, propanolol has E H = 0.75 , yielding
17.9ml
Cl H = ----------------------------------------------------min Kg body weight
and
( Cl H )
int
71.4ml
= ----------------------------------------------------min Kg body weight
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9-8
Clearance
Kidney excretion of
unchanged drug
where
Er
Cl
Er = --------r
Qr
(EQ 9-29)
f u ( Cl r ) int
Er = --------------------------------------Q r + f u ( Cl r ) int
(EQ 9-30)
and
int
Qr
( Cl r )
int
1.89ml
= ----------------------------------------------------min Kg body weight
( Cl r )
E r = 0.09
int
= 0
, to one, when
, yielding
Qr = 0
or
1.72ml
Cl r = ---------------------------------------------------min Kg body weight
Cl r Cl c r
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9-9
Clearance
Cl H
(EQ 9-31)
Q H
F R = ---------QH
is the new flow rate over the old flow rate, the fractional change in blood
The equation predicts that, for any given decrease in blood perfusion rate, drugs
having a large normal extraction ratio will experience a proportionally greater
reduction in clearance than drugs having a small normal extraction ratio.
Liver blood flow can be reduced by congestive heart failure, for example. The
intrinsic hepatic clearance can be represented by the inherent activity of the
enzymes responsible for drug metabolism.
9.6.2
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9-10
Clearance
Fi
Cl
-----------H- = ----------------------------------1 + EH ( F i 1 )
Cl H
where
f u ( Cl int )
F i = ------------------------------f u ( Cl int )
(EQ 9-32)
9.6.3
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9-11
Clearance
Cl r = f u GFR . It is likely that the drug is filtered only, in this case, . It is also possible that
secretion and reabsortion balance and cancel each orther out but are still occurring. The actual
clearance of the drug may be low as the drug may be bound to plasma protiens or red blood
cells.
11. Cl r > f u GFR .
Net active secretion is infered in this case. These active mechanisms are non-
specific and consequently, drugs actively secreted compete with each other. Secretion, if it
occurs, occurs on the unbound drug and thus is also effected by changes in free fraction. In
cases where secretion is very rapid and as a consequence, virtually all of the drug is removed by
the single pass through the kidney (Er ~1), the disssociation of the drug from the protien or out
of the red blood cells is not a hinderance. Some reabsorption may occur but it is less than secretion.
12. Cl r < f u GFR .
Net active reabsorbtion is infered in this case. Active reabsorption occurs for
many exogenous compounds, including glucose and vitamins. For many compounds, reabsorption is passive, occurring only as a consequence of the concentration gradient produced as water
is removed from the urine as is proceeds down the renal tubule. Since the membrane is lipoidal
in nature, polar compounds, ionized acids and ionized bases are less likely to be reabsorbed.
Thus changing the pH of the urine would result in changing the reabsorption characteristics of
weakly acidic or basic drugs.
For low molecular weight drugs (<2,000 dalton) , filtration always occurs. Active
secretion, active reabsorption and passive reabsorption may occur.
It has been found that renal blood flow is little affected by changes in blood flow
elsewhere. However, in chronic renal dysfunction there are two effects which
exhibit a parallel decline. One is a decrease in glomerular filtration rate (GFR), as
measured by Cl cr , and the other is the net secretion of drugs into the kidney
tubules. Note that p-amino hippurate (PAH) clearance measures the sum of both
effects.
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9-12
Clearance
For any given drug, equation 9-26 predicts that alterations in both the renal blood
perfusion rate (as manifest by the GFR) and the intrinsic renal clearance will cause
a change in drug clearance. A general equation may be derived relating the ratio of
renal clearances at two different blood flow rates and two different intrinsic renal
clearances.
Cl
-----------r = F i
Cl r
(EQ 9-33)
where F i is the fractional change in drug unbound times the fractional change in
intrinsic renal clearance.
In this case,
f u
F i = ------F
fu
R
where
FR
(EQ 9-34)
Thus, equation 9-33 shows that the renal clearance of a drug is reduced by a constant fraction, independent of the renal extraction ratio ( E r ) . This fractional
decrease can be estimated by changes in creatinine clearance:
Cl cr
FR = -----------Cl cr
where
Cl cr
(EQ 9-35)
(EQ 9-36)
This equation shows why, in cases of chronic renal dysfunction, a change in the
measured creatinine clearance indicated a likely change in drug renal clearance.
Hence, dosage adjustments are made on this basis, particularly for drugs predominantly eliminated by renal filtration (e.g., gentamicin, digoxin).
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9-13
Clearance
(EQ 9-37)
When a drug has a high extraction ratio, E 1 , then equation 9-26 becomes
F Cl F R
(EQ 9-38)
and when a drug has a low extraction ratio, E 0 , then equation 9-26 becomes
F Cl F I
(EQ 9-39)
Thus, the clearance of drugs with a high extraction ratio are more effected by physiological changes in flow of blood to the clearing organ, while drugs with a low
extraction ratio are more effected by physiological changes in the function of the
organ.
9.8.1
PLASMA/BLOOD RATIO
Calculation of Extraction Ratio requires measurement in whole blood by definition. Since most clinical measurements are done in plasma, knowledge of the
plasma/blood ratio is necessary. Blood in made up of plasma and red blood cells
(RBCs). Thus the amount of drug in the blood is made up of the amount of drug in
the plasma and the amount of drug in the RBCs.
C b Vb = C p Vp + C rbc V rbc
where
(EQ 9-40)
C x V x = AMOUNT x
and
If we define the ratio of the concentration of the drug in the RBCs to the concentration of the free drug in plasma as
C rbc
= -------------fu C p
(EQ 9-41)
and
V rbc = H V b
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(EQ 9-42)
9-14
Clearance
Vp = ( 1 H) Vb
(EQ 9-43)
Pluging equation 9-41 thru equation 9-43 into equation 9-40 results in:
Cb Vb = ( 1 H ) V b Cp + f u H Vb Cp
(EQ 9-44)
H 1 + ( Cb C p )
= ----------------------------------------fu H
(EQ 9-45)
(EQ 9-46)
Thus equation 9-46 determines the affinity of the drug for the RBCs. Drugs with a
high affinity for the RBCs should result in a smaller volume of distribution.
For drugs that are primarily filtered by the glomeruli, the renal extraction ratio is:
GFR f u C p
Rate of filtration - = ------------------------------E rf = ----------------------------------------------Rate of presentation
Qr Cb
(EQ 9-47)
(EQ 9-48)
Thus:
1.
Cl
Qr
If the the ratio of --------r to calculated Erf from equation 9-48 is one, it is likely that the drug is
filtered only.
13.
Cl
If the the ratio of --------r to calculated Erf from equation 9-48 is greater than one, active secretion
Qr
Cl
If the the ratio of --------r to calculated Erf from equation 9-48 is less than one, active reabsorbQr
Basic Pharmacokinetics
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9-15
Clearance
9.8.2
(EQ 9-49)
Cl pw
Cl
K = Cl
------ = -------b- = -------------u
V
Vb
Vpw u
(EQ 9-50)
where b = blood and pwu = unbound plasma water. Clearance of drug from blood
(Clb) is useful in considering drug extraction in the eliminating organs. Volume
and clearance terms based on unbound drug concentration are particularly useful
in therapeutics, because only the unbound drug is thought to cause the therapeutic
action.
9.8.3
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9-16
Clearance
9.9 Problems
For each of the problems, do questions A through R now and S through W after
completing chapter 10. In doing questions S through W, please try to obtain a
plasma concentration of free drug within 120 % of normal
Cp
ss
min free
Cp
ss
max free
and 80 % of
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9-17
Clearance
Acebutolol
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 1)
AHFS 00:00.00
GPI: 0000000000
Piquette-Miller, M., et. al., Effect of aging on the pharmacokinetics of acebutolol enantiomers, Journal of Clinical Pharmacology, Vol. 32, (1992), p. 148 - 156. Kukes, VG; Gneushev ET; Mamedov TS; Gneusheva IA; Acebutolol and diacetolol: thier binding to plasma and erythrocytes and secretion with saliva. Farmakol-Toksikol. 1991 Jan-Feb; 54(1)
Acebutolol is a beta-adrenergic blocking agent which is often used in the treatment of hypertension.(Use Qr = 72 L/hr;
PROBLEM TABLE 9 - 1. Acebutolol
Patient Condition
Normal
Normal
Dose(mg)
200
400
0.4
fu
0.867
1.93
Vd (L)
k (hr-1)
T 1/2 (hr)
5.5
%Clr
40
%Clnr
60
AUC (mg/L*hr)
3.97
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
12
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Qh = 90 L/hr)
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9-18
Clearance
Patient Condition
Normal
Normal
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
Dose(mg)
200
400 BID
400 BID
400 BID
400 BID
200 QID
FRR
0.5
FIR
0.5
0.5
FRH
0.5
FIH
0.5
0.4
fu
0.867
1.93
Vd (L)
160
k (hr-1)
0.126
0.101
0.102
0.12
0.091
T 1/2 (hr)
5.5
6.87
6.77
5.89
7.64
%Clr
40
25
26.1
42.9
55.5
%Clnr
60
75
73.9
57.1
44.6
AUC (mg/L*hr)
3.97
9.93
9.78
8.51
5.5
Cl tot (L/hr)
20.2
16.1
16.4
18.8
14.5
Cl h (L/hr)
12.1
12.1
12.1
10.7
6.5
Cl r (L/hr)
8.1
4.03
4.27
8.1
8.1
Eh
0.126
Er
0.112
0.8
0.81
0.93
0.72
12
12
12
12
2.18
1.75
1.77
2.04
0.785
g
------ mL
1.11
1.24
1.23
1.15
1.03
g
------ mL
0.57
0.72
0.71
0.61
0.80
ss g
-------min free mL
0.25
0.37
0.36
0.28
0.6
P
Q
Cl h
Cl r
int
int
(L/hr)
16
(L/hr)
10.5
FCL
(hr)
N
U
Cp
ss
max free
V
Cp
W
Cp
ss
avg free
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9-19
Clearance
Bisoprolol
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 2)
AHFS 00:00.00
GPI: 0000000000
Kirch, W., et. al., Pharmacokinetics of bisoprolol during repeated oral administration to healthy volunteers and patients with kidney or liver disease, Clinical Pharmacokinetics, Vol. 13, (1987), p. 110 - 117.
Bisoprolol (comes as 5 and 10 mg tablets) is a - selective adrenergic antagonist. It is used in the treatment of hypertension and angina pectoris.(Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 2. Bisoprolol
Patient Condition
Normal
Normal
Dose(mg)
10
10 TID
0.7
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
10
%Clr
50
%Clnr
50
AUC (mg/L*hr)
0.661
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
W
Cp
ss g
-------avg free mL
ss
g
------min free mL
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9-20
Clearance
Patient Condition
Normal
Normal
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
Dose(mg)
10
10
10
10
10
10
FRR
0.5
FIR
0.5
0.5
FRH
0.5
FIH
0.5
0.9
fu
0.7
Vd (L)
152.8
k (hr-1)
0.0693
0.052
0.0526
0.067
0.0525
T 1/2 (hr)
10
13.3
13.2
10.3
13.2
%Clr
50
33.3
34
51.3
66
%Clnr
50
66.7
66
48.7
34
AUC (mg/L*hr)
0.661
0.85
0.87
0.69
0.87
Cl tot (L/hr)
10.6
7.94
8.0
10.3
8.0
Cl h (L/hr)
5.3
5.3
5.3
5.0
2.7
Cl r (L/hr)
5.3
2.65
2.8
5.3
5.3
Eh
0.055
Er
0.074
0.75
0.76
0.97
0.76
12
12
12
P
Q
Cl h
Cl r
int
int
(L/hr)
5.6
(L/hr)
5.7
FCL
(hr)
N
U
Cp
0.8
0.9
0.9
0.78
0.91
0.108
0.099
0.098
0.11
0.098
g
------ mL
0.083
0.073
0.073
0.085
0.073
g
------ mL
0.062
0.052
0.052
0.064
0.052
ss g
-------max free mL
V
Cp
W
Cp
ss
avg free
ss
min free
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9-21
Clearance
Cefonicid
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 3)
AHFS 00:00.00
GPI: 0000000000
Fillastre, J., et. al., Pharmacokinetics of cefonicid in uraemic patients, Journal of Antimicrobial Chemotherapy, Vol. 18, (1986),
p. 203 - 211.
Cefonicid is a beta-lactamase resistant cephalosporin which is useful in treating many infections caused by Gram-positive and Gram-negative organisms. Cefonicid is 80% renally excreted.(Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 3. Cefonicid
Patient Condition
Normal
Normal
Dose(mg)
1000
1000 TID
fu
0.06
Vd (L)
k (hr-1)
T 1/2 (hr)
5.3
%Clr
80
%Clnr
20
AUC (mg/L*hr)
654
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
W
Cp
ss g
-------avg free mL
ss
g
------min free mL
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Clearance
Patient Condition
Normal
Normal
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
Dose(mg)
1000
1000
1000
1000
1000
1000
FRR
0.5
FIR
0.5
0.5
FRH
0.5
FIH
0.5
fu
0.06
Vd (L)
11.7
k (hr-1)
0.131
0.078
0.079
0.131
0.118
T 1/2 (hr)
5.3
8.8
8.8
5.3
5.9
%Clr
80
66.7
66.9
80
88.9
%Clnr
20
33.3
33.1
20
11.1
AUC (mg/L*hr)
654
1090
1083
654
727
Cl tot (L/hr)
1.53
0.917
0.93
1.5
1.4
Cl h (L/hr)
0.3
0.31
0.31
0.3
0.15
Cl r (L/hr)
1.22
0.612
0.62
1.22
1.22
Eh
0.0032
Er
0.017
0.6
0.6
0.9
12
12
1.51
1.4
1.4
1.51
1.36
g
------ mL
7.9
8.4
8.4
7.9
8.4
g
------ mL
4.9
5.5
5.4
4.9
5.4
ss g
-------min free mL
2.8
3.3
3.3
2.8
3.3
P
Q
Cl h
Cl r
(L/hr)
5.11
(L/hr)
20.7
int
int
FCL
(hr)
N
U
Cp
ss
max free
V
Cp
W
Cp
ss
avg free
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-23
Clearance
Cefpirome
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 4)
AHFS 00:00.00
GPI: 0000000000
Lameire, N., et. al., Single-dose pharmacokinetics of cefpirome in patients with renal impairment, Clinical Pharmacology and
Therapeutics, Vol. 52, (1992), p. 24 - 30.
Cefpirome
Patient Condition
Normal
Normal
Dose(mg)
2000 IV
2000 TID
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
2.6
%Clr
85
%Clnr
15
AUC (mg/L*hr)
342
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
W
Cp
ss g
-------avg free mL
ss
g
------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-24
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-25
Clearance
Cefprozil
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 5)
AHFS 00:00.00
GPI: 0000000000
Shyu, W., et. al., Pharmacokinetics of cefprozil in healthy subjects and patients with renal impairment, Journal of Clinical Pharmacology, Vol. 31, (1991), p. 362 - 371.
Patient Condition
Normal
Dose(mg)
1000
0.95
fu
0.7
Vd (L)
k (hr-1)
T 1/2 (hr)
1.2
%Clr
75
%Clnr
25
AUC (mg/L*hr)
58.1
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Cefprozil
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-26
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-27
Clearance
Chloramphenicol
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 6)
AHFS 00:00.00
GPI: 0000000000
Ambrose, P., Clinical pharmacokinetics of chloramphenicol and chloramphenicol succinate, Clinical Pharmacokinetics, Vol. 9,
(1984), p. 222 - 238.
Chloramphenicol succinate is a prodrug which is converted in vivo to the active form, chloramphenicol.
PROBLEM TABLE 9 - 6.
Patient Condition
Normal
Dose(mg)
1000
fu
0.4
Vd (L/kg)
k (hr-1)
T 1/2 (hr)
0.6
%Clr
30
%Clnr
70
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
2.8
(L/hr)
int
FCL
Normal
(L/hr)
int
Chloramphenicol
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-28
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-29
Clearance
Enalapril
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 7)
AHFS 00:00.00
GPI: 0000000000
Ohnishi, A., et. al., Kinetics and dynamics of enalapril in patients with liver cirrhosis, Clinical Pharmacology and Therapeutics,
Vol. 45, (1989), p. 657 - 665.
Enalapril is an ACE inhibitor which is a prodrug that is metabolized in the liver to the active metabolite, enalaprilat.
PROBLEM TABLE 9 - 7. Enalapril
Patient Condition
Normal
Normal
Dose(mg)
10 mg po
10 BID1
0.65
fu
0.55
Vd (L)
k (hr-1)
T 1/2 (hr)
0.63
%Clr
27
%Clnr
73
AUC (mg/L*hr)
0.123
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-30
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-31
Clearance
Enoxacin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 8)
AHFS 00:00.00
GPI: 0000000000
Somogyi, A., and Bochner, F., The absorption and disposition of enoxacin in healthy subjects, Journal of Clinical Pharmacology, Vol. 28, (1988), p. 707 - 713.
Enoxacin is a fluorinated quinolone which is used to treat infections caused by gram-negative organisms and
Pseudomonoas aeruginosa.
PROBLEM TABLE 9 - 8.
Enoxacin
Patient Condition
Normal
Normal
Dose(mg)
400
200 bid
0.9
fu
0.8
Vd (L)
k (hr-1)
T 1/2 (hr)
7.75
%Clr
60
%Clnr
40
AUC (mg/L*hr)
15.61
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
12
U
Cp
ss
g
------max free mL
V
Cp
W
Cp
ss g
-------avg free mL
ss
g
------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-32
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-33
Clearance
Enprofylline
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 9)
AHFS 00:00.00
GPI: 0000000000
Nadai, M., et. al, Dose-dependent pharmacokinetics of enprofylline and its renal handling in rats, Journal of Pharmaceutical
Sciences, Vol. 80, No. 7, (1991), p. 648 - 651
PROBLEM TABLE 9 - 9.
Patient Condition
Normal
Normal
Dose(mg/kg)
2.5
2.5 TID
fu
0.4
Vd (L/kg)
k (hr-1)
T 1/2 (hr)
0.36
%Clr
90
%Clnr
10
AUC (mg/L*hr)
3.6
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-34
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-35
Clearance
Erythromycin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 10)
AHFS 00:00.00
GPI: 0000000000
Erythromycin
Patient Condition
Normal
Normal
Dose(mg)
300
300 TID
.8
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
10
%Clnr
90
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
0.06
0.06
0.12
0.06
0.18
57
57
100
57
150
16.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-36
Clearance
Erythromycin
Patient Condition
Normal
Normal
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
Dose(mg)
300
300
300
200
300
200
FRR
0.5
FIR
0.5
0.5
FRH
0.5
FIH
0.5
.8
fu
0.06
0.06
0.12
0.06
0.18
Vd (L)
57
57
100
57
150
k (hr-1)
0.255
0.242
0.235
0.227
0.075
T 1/2 (hr)
2.71
2.85
2.92
3.05
9.27
%Clr
10
5.3
3.1
11.2
37
%Clnr
90
94.7
96.9
88.8
63
AUC (mg/L*hr)
14.5
17.4
6.7
18.5
14.2
Cl tot (L/hr)
16.5
13.8
23.7
13.0
11
Cl h (L/hr)
13.1
13.1
23.4
11.5
7.02
Cl r (L/hr)
1.45
0.73
0.73
1.45
4.19
Eh
0.136
Er
0.020
0.95
1.63
0.89
0.77
24
2.94
2.79
2.74
2.63
2.59
g
------ mL
0.29
0.30
0.23
0.30
0.23
g
------ mL
0.12
0.13
0.10
0.14
0.11
0.038
0.042
0.034
0.049
0.038
P
Q
Cl h
Cl r
(L/hr)
252
(L/hr)
24.7
int
int
FCL
(hr)
N
U
Cp
ss
max free
V
Cp
W
Cp
ss
avg free
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-37
Clearance
Fleroxacin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 11)
AHFS 00:00.00
GPI: 0000000000
Singlas, E., et. al., Disposition of fleroxacind, a new trifluoroquinolone, and its metabolites - pharmacokinetics in renal failure
and influence of haemodialysis, Clinical Pharmacokinetics, Vol. 19, No. 1, (1990), p. 67 - 79.
Fleroxacin is a trifluorinated quinolone with activity against a variety of gram-negative and gram-positive organisms.
Fleroxacin
Patient Condition
Normal
Normal
Dose(mg)
400
200 tid
0.95
fu
0.5
1.45
Vd (L)
k (hr-1)
T 1/2 (hr)
14
%Clr
65
%Clnr
35
AUC (mg/L*hr)
92
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-38
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-39
Clearance
Fosinopril
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 12)
AHFS 00:00.00
GPI: 0000000000
Hui, K., et. al., Pharmacokinetics of fosinopril in patients with various degrees of renal function, Journal of Clinical Pharmacology and Therapeutics, Vol. 49, No. 4, (1991), p. 457 - 466.
Fosinopril is an angiotensin converting enzyme inhibitor which is a prodrug that is metabolized to active form, fosinoprilat.
PROBLEM TABLE 9 - 12.
Fosinopril
Patient Condition
Normal
Normal
Dose(mg)
7.5 IV
20 po qd
1 (Oral
0.36)
fu
0.01
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
100
AUC (mg/L*hr)
5.1
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
24
U
Cp
ss
g
------max free mL
V
Cp
W
Cp
ss g
-------avg free mL
ss
g
------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-40
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
Fosinopril
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-41
Clearance
Glutathione
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 13)
AHFS 00:00.00
GPI: 0000000000
Mulders, T., et. al., Characterization of glutathione conjugation in humans: stereoselectivity in plasma elimination pharmacokinetics and urinary excretion of (R)- and (S)-2-bromoisovalerylurea in healthy volunteers, Clinical Pharmacology and Therapeutics, Vol. 53, (1993), p. 49 - 58.
Patient Condition
Normal
Normal
Dose(mg)
600
500 tid
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
4.4
%Clr
35
%Clnr
65
AUC (mg/L*hr)
276
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-42
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
Glutathione
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-43
Clearance
Guanadrel
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 14)
AHFS 00:00.00
GPI: 0000000000
Halstenson, C., et. al., Disposition of guanadrel in subjects with normal and impaired renal function, Journal of Clinical Pharmacology, Vol. 29, (1989), p. 128 - 132.
Patient Condition
Normal
Normal
Dose(mg)
25 mg po
25 BID
fu
0.8
Vd (L)
k (hr-1)
T 1/2 (hr)
3.7
%Clr
40
%Clnr
60
AUC (mg/L*hr)
0.234
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
12
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-44
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
Guanadrel
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-45
Clearance
Monoxidine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 15)
AHFS 00:00.00
GPI: 0000000000
Kirch, W., Hutt, H., and Plnitz, V., The influence of renal function on clinical pharmacokinetics of monoxidine, Clinical Pharmacokinetics, Vol. 15, (1988), p. 245 - 253.
Monoxidine
Patient Condition
Normal
Normal
Dose(mg)
0.25 IV
0.25 tid
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
2.75
%Clr
95
%Clnr
AUC (mg/L*hr)
0.05
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-46
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
Monoxidine
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-47
Clearance
Nalmefene
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 16)
AHFS 00:00.00
GPI: 0000000000
Dixon, R., et. al., Nalmefence: safety and kinetics after single and multiple oral doses of a new opiod antagonist, Journal of
Clinical Pharmacology, Vol. 27, (1987), p. 233 - 239.
Nalmefene is a pure opiod antagonist which is currently being investigated for use.
Nalmefene
Patient Condition
Normal
Dose(mg)
20 IV
0.6 oral
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
9.8
%Clr
70
%Clnr
30
AUC (mg/L*hr)
0.3
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FRR=0.5
(L/hr)
int
Normal
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-48
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
Nalmefene
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-49
Clearance
Nitrendipine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 17)
AHFS 00:00.00
GPI: 0000000000
Dylewicz, P, et. al, Bioavailability and elimination of nitrendipine in liver disease, European Journal of Clinical Pharmacology,
Vol, 32, (1987), p. 563 - 568.
Nitrendipine
Patient Condition
Normal
Normal
Dose(mg)
5 IV
25 po BID
1 (oral 0.2)
fu
0.05
Vd (L)
k (hr-1)
T 1/2 (hr)
11.7
%Clr
0.1
%Clnr
99.9
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
90
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-50
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
Nitrendipine
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-51
Clearance
Ofloxacin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 18)
AHFS 00:00.00
GPI: 0000000000
Lamerire, N., et. al., Ofloxacin pharmacokinetics in chronic renal failure and dialysis, Clinical Pharmacokinetics, Vol. 21, No.
4, (1995), p. 357 - 371.
PROBLEM TABLE 9 - 18.
Ofloxacin
Patient Condition
Normal
Normal
Dose(mg)
300
300
0.93
fu
0.74
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
97
%Clnr
AUC (mg/L*hr)
28.47
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
12
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-52
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
Ofloxacin
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-53
Clearance
Omeprazole
(Problem 9 - 19)
AHFS 00:00.00
GPI: 0000000000
Omeprazole
Patient Condition
Normal
Normal
Dose(mg)
10
10 BID
0.5
fu
0.04
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
100
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FIH=0.5
0.75
0.06
0.08
30
12
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
FRH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
Omeprazole
Patient Condition
Normal
Normal
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
Dose(mg)
10
10
10
10
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-54
Clearance
FRR
0.5
FIR
0.5
0.5
FRH
0.5
FIH
1.5
0.5
0.75
0.5
fu
0.04
Vd (L)
30
k (hr-1)
0.347
0.347
0.493
0.31
0.184
T 1/2 (hr)
1.41
2.2
3.8
%Clr
%Clnr
100
AUC (mg/L*hr)
0.48
0.48
0.338
0.53
0.68
Cl tot (L/hr)
10.4
10.4
14.8
9.38
5.5
Cl h (L/hr)
10.4
10.4
14.8
9.38
5.5
Cl r (L/hr)
Eh
0.108
Er
1.42
0.90
0.53
12
P
Q
Cl h
Cl r
(L/hr)
291.5
(L/hr)
int
int
FCL
0.06
(hr)
N
U
Cp
2.83
2.71
3.2
0.0076
0.0076
0.0051
0.0079
0.011
g
------ mL
0.0032
0.0032
0.0025
0.0035
0.0045
g
------ mL
0.00095
0.00095
0.00099
0.0012
0.0012
ss g
-------max free mL
V
Cp
W
Cp
ss
avg free
ss
min free
0.08
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-55
Clearance
Piperacillin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 20)
AHFS 00:00.00
GPI: 0000000000
Johnson, C., et. al., Single-dose pharmacokinetics of piperacillin and tazobactam in patients with renal disease, Clinical Pharmacology and Therapeutics, Vol. 51, (1992), p. 32 - 41.
Patient Condition
Normal
Normal
Dose(mg)
3000
2000 qid
fu
0.82
Vd (L)
k (hr-1)
T 1/2 (hr)
0.95
%Clr
75
%Clnr
25
AUC (mg/L*hr)
276
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-56
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
Piperacillin
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-57
Clearance
Piroxicam
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 21)
AHFS 00:00.00
GPI: 0000000000
Boudinot, S., Funderburg, E., and Boudinot, F., Effects of age on the pharmacokinetics of piroxicam in rats, Journal of Pharmaceutical Sciences, Vol. 82, No. 3, (1993), p. 254 - 257.
Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) commonly used in the treatment of arthritis.
Piroxicam
Patient Condition
Normal
Normal
Dose(mg)
70
20 qd
fu
0.007
Vd (L)
k (hr-1)
T 1/2 (hr)
50
%Clr
%Clnr
95
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-58
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
Piroxicam
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-59
Clearance
Quinidine
(Problem 9 - 22)
AHFS 00:00.00
GPI: 0000000000
Quinidine sulfate is used to treat ventricular and supraventricular arrythmias and is available in 200 and 300 mg tablets.
It is known to bind to -acid glycoprotein (AAG), which is an acute phase reactant. AAG rises in trauma, inflamation,
malignancy and stress and falls in hepatic disease, nephrotic syndrome and malneurtrition for example.(Use Qr = 72 L/
hr; Qh = 90 L/hr)
Quinidine
Patient Condition
Normal
Normal
Dose(mg/kg)
10
10 TID
0.7
fu
0.2
0.83
Vd (L/kg)
2.6
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr/kg)
Cl h (L/hr/kg)
0.20
Cl r (L/hr/kg)
0.056
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
0.10
0.25
0.15
0.3
2.0
2.75
2.2
3.0
6.4
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
1
8
(hr)
N
U
Cp
ss
max free
V
Cp
W
Cp
g
------ mL
MTC
1.7
ss g
-------avg free mL
ss
min free
g
------ mL
MEC
0.37
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-60
Clearance
Quinidine
Patient Condition
Normal
Normal
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
Dose(mg)
10
10
10
10
10
FRR
0.5
FIR
0.25
0.5
0.75
1.5
FRH
0.5
FIH
0.5
1.25
0.75
0.5
0.7
fu
0.20
0.10
0.25
0.15
0.30
0.83
Vd (L)
2.6
2.0
2.75
2.2
3.0
k (hr-1)
0.098
0.057
0.101
0.087
0.061
T 1/2 (hr)
12.1
6.9
7.9
11.3
%Clr
22
12.3
10
22
46
%Clnr
78
87.7
90
78
54
AUC (mg/L*hr)
27.3
61.3
20.6
36.5
19.0
Cl tot (L/hr)
0.256
0.114
0.28
0.19
0.18
Cl h (L/hr)
0.20
0.10
0.25
0.15
0.1
Cl r (L/hr)
0.056
0.014
0.028
0.04
0.08
Eh
0.0021
Er
0.00078
0.45
1.1
0.75
0.72
1.3
0.66
1.16
1.0
0.71
0.82
0.79
0.95
0.79
0.75
0.57
0.63
0.65
0.56
0.59
0.37
0.5
0.44
0.39
0.46
P
Q
Cl h
Cl r
(L/hr)
1.0
(L/hr)
0.28
int
int
FCL
(hr)
N
U
Cp
ss
max free
V
Cp
W
Cp
ss
avg free
ss
min free
g
------ mL
MTC
1.7
g
------ mL
g
------ mL
MEC
0.3
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-61
Clearance
Tazobactam
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 23)
AHFS 00:00.00
GPI: 0000000000
Johnson, C., et. al., Single-dose pharmacokinetics of piperacillin and tazobactam in patients with renal disease, Clinical Pharmacology and Therapeutics, Vol. 51, (1992), p. 32 - 41.
Patient Condition
Normal
Normal
Dose(mg)
375 IV
375 qid
fu
0.96
Vd (L)
k (hr-1)
T 1/2 (hr)
0.89
%Clr
68
%Clnr
32
AUC (mg/L*hr)
30.3
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
Tazobactam
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-62
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-63
Clearance
Theophylline
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 24)
AHFS 00:00.00
GPI: 0000000000
Wagner, J., Theophylline - pooled Michaelis-Menten parameters and implications, Clinical Pharmacokinetics, Vol. 10, (1985),
p. 432 - 442.
PROBLEM TABLE 9 - 24. Theophylline
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-64
Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
Theophylline
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
9-65
Clearance
Tolrestat
(Problem 9 - 25)
AHFS 00:00.00
GPI: 0000000000
Troy, S., et. al., The effect of renal disease on tolrestat pharmacokinetics, Clinical Pharmacology and Therapeutics, Vol. 51,
(1992), p. 271 - 277.
Tolrestat is an aldose reductase inhibitor used in the treatment of diabetic neuropathy, diabetic nephropathy, and diabetic retinopathy. (Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 25.
Tolrestat
Patient Condition
Normal
Normal
Dose(mg)
200
200 tid
0.8
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
10.6
%Clr
25
%Clnr
40 bile 35 metab.
AUC (mg/L*hr)
86
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
N
U
Cp
ss
g
------max free mL
V
Cp
W
Cp
ss g
-------avg free mL
ss
g
------min free mL
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Clearance
Tolrestat
Patient Condition
Normal
Normal
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
Dose(mg)
200
200 TID
200 TID
200 TID
200 TID
200 BID
FRR
0.5
FIR
0.5
0.5
FRH
0.5
FIH
0.5
0.8
fu
Vd (L)
28.5
k (hr-1)
0.0654
0.057
0.057
0.065
0.041
T 1/2 (hr)
10.6
12.1
12.1
10.7
16.9
%Clr
25
14.3
14.3
25.3
39.8
%Clnr
75
85.7
85.7
74.7
60.2
AUC (mg/L*hr)
86
98.3
98.2
87
137
Cl tot (L/hr)
1.86
1.63
1.63
1.84
1.17
Cl h (L/hr)
1.4
1.4
1.4
1.4
0.7
Cl r (L/hr)
0.46
0.23
0.47
0.47
0.47
Eh
0.0155
Er
0.0065
0.88
0.88
0.99
0.63
12
0.75
0.66
0.66
0.75
0.71
g
------ mL
13.8
15.3
15.3
13.9
14.4
g
------ mL
10.8
12.3
12.3
10.9
11.4
g
------ mL
8.2
9.6
9.7
8.3
8.8
P
Q
Cl h
Cl r
(L/hr)
1.42
(L/hr)
0.47
int
int
FCL
(hr)
N
U
Cp
ss
max free
V
Cp
W
Cp
ss
avg free
ss
min free
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Clearance
Vancomycin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 9 - 26)
AHFS 00:00.00
GPI: 0000000000
Macais, W., Meuller, B., and Scarim, S., Vancomycin pharmacokinetics in acute renal failure; preservation of nonrenal clearance, Clinical Pharmacology and Therapeutics, Vol., 50, (1991), p. 688 - 694.
Vancomycin is a glycopeptide antibiotic used in the treatment of infections caused by Gram-positive organisms.
PROBLEM TABLE 9 - 26.
Vancomycin
Patient Condition
Normal
Normal
Dose(mg)
1000
500 QID
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
70
%Clnr
30
AUC (mg/L*hr)
543
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
0.44
(L/hr)
int
FCL
FIR=0.5
(L/hr)
int
FRR=0.5
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
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Clearance
Patient Condition
A
Dose(mg)
fu
Vd (L)
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
Cl r (L/hr)
Eh
Er
P
Q
Cl h
Cl r
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
(L/hr)
int
FCL
Normal
(L/hr)
int
Normal
Vancomycin
(hr)
N
U
Cp
ss g
-------max free mL
ss
Cp
g
------avg free mL
Cp
ss g
-------min free mL
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Clearance
Xipamide
(Problem 9 - 27)
AHFS 00:00.00
GPI: 0000000000
Knauf, H, et. al., Xipamide disposition in liver cirrhosis, Clinical Pharmacology and Therapeutics, Vol. 48, No. 6, (1990), p. 328
- 632.
Xipamide is a diuretic that has been used in the treatment of congestive heart failure, hypertension, advanced renal failure, and hepatic edema.(Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 27.
Xipamide
Patient Condition
Normal
Normal
Dose(mg)
40
40 QID
0.8
fu
0.01
Vd (L)
21
k (hr-1)
T 1/2 (hr)
%Clr
%Clnr
AUC (mg/L*hr)
Cl tot (L/hr)
Cl h (L/hr)
1.38
Cl r (L/hr)
0.72
Eh
Er
P
Q
Cl h
Cl r
FRH=0.5
FIH=0.5
0.01
0.02
0.01
0.025
(L/hr)
FCL
FIR=0.5
(L/hr)
int
int
FRR=0.5
(hr)
N
U
Cp
ss g
-------max free mL
V
Cp
ss g
-------avg free mL
Cp
ss g
-------min free mL
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Clearance
Xipamide
Patient Condition
Normal
Normal
FRR=0.5
FIR=0.5
FRH=0.5
FIH=0.5
Dose(mg)
40
40 QID
40 QID
20 QID
40 QID
20 QID
FRR
0.5
FIR
0.5
0.5
2.5
FRH
0.5
FIH
0.5
0.8
fu
0.01
0.01
0.02
0.01
0.025
Vd (L)
21
k (hr-1)
0.1
0.083
0.146
0.1
0.118
T 1/2 (hr)
6.9
8.4
4.7
7.0
5.9
%Clr
34
21
12
35
72
%Clnr
66
79
88
65
28
AUC (mg/L*hr)
15.2
18.4
7.8
15.4
6.5
Cl tot (L/hr)
2.1
1.74
3.1
2.1
2.5
Cl h (L/hr)
1.38
1.38
2.71
1.36
0.7
Cl r (L/hr)
0.72
0.36
0.36
0.72
1.8
Eh
0.0144
Er
0.01
0.83
1.46
1.18
P
Q
Cl h
Cl r
(L/hr)
140
(L/hr)
73
int
int
FCL
U
Cp
0.87
0.71
0.847
0.86
0.034
0.039
0.034
0.034
0.038
g
------ mL
0.025
0.031
0.026
0.025
0.027
g
------ mL
0.019
0.024
0.019
0.019
0.019
ss g
-------max free mL
V
Cp
W
Cp
(hr)
ss
avg free
ss
min free
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CHAPTER 10
OBJECTIVES
1.
Given population average patient data, the student will devise (V) dosage regimens which will maintain plasma concentrations of drug within the therapeutic
range.
2.
Given specific patient information, the patient will justify (VI) dosage regimen
recommendations.
3.
Given patient information regarding organ function, the student will devise (V)
and justify (VI) dosage regimen recommendations for the compromised patient.
4.
The student will write (V) a professional consult using the above calculations
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THERAPEUTIC RANGE
The pharmacokinetics of a drug determine the blood concentration achieved from
a prescribed dosing regimen. During multiple drug dosing, the blood concentration
will reflect the drug concentration at the receptor site; and it is the receptor site
concentration that determines the intensity of the drugs effect. Therefore, in order
to predict a patients response to a drug regimen, both the pharmacokinetics and
pharmacological response characteristics of the drug must be understood.
There exists a fundamental relationship between drug pharmacokinetics and pharmacologic response. The relationship between response and ln-concentration is
sigmoidal. A threshold concentration of drug must be attained befor any response
is ellicited at all. Therapy is accheived when the desired effect is attained because
the required concentration has been reached. That concentration would set the
lower limit of utility of the drug, and is called Effective Concentration (MEC).
Most drugs are not clean, that is exhibit only the desired therapeutic response.
They also exhibit undesired side effects, sometimes called toxic effects at a higher,
hopefully a lot higher, concentration. At some concentration, these toxic side
effects become become intollerable. That concentration, or one below it, would
set the upper limit of utility for the drug and is called the Maximum Therapeutic
Concentration or Minimum Toxic Concentration (MTC). Patient studies have
generated upper (MTC) and lower (MEC) plasma concentration ranges that are
deemed safe and effective in treating specific disease states. These concentrations
are known as the therapeutic range for the drug (see Table 10-1).When a drug is
administered at a fixed dosage to numerous subjects, the blood concentrations
achieved vary greatly due to biological variation. However it is possible to have a
reasomable
Clinically, digoxin concentrations below 0.8 ng ml will elicit a subtherapeutic
effect. Alternatively, when the digoxin concentration exceeds 2.0 ng ml side
effects occur (nausea and vomiting, abdominal pain, visual disturbances). Drugs
like digoxin possess a narrow therapeutic index because the concentrations that
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may produce toxic effects are close to those required for therapeutic effects. The
importance of considering both pharmacokinetics and pharmacodynamics is clear.
TABLE 10-1. Average
DRUG
RANGE
digoxin
0.8-2.0 ng ml
gentamicin
2-10 g ml l
lidocaine
1-4 g ml
lithium
0.4-1.4 mEq L
phenytoin
10-20 g ml
phenobarbitol
10-30 g ml
procainamide
4-8 g ml
quinidine
3-6 g ml
theophylline
10-20 g ml
Drug-drug interaction
patient disease state
physiological states such as age, weight, sex
drug absorption variation
differences in the ability of a patient to metabolize and eliminate the drug
If we were to give an identical dose of drug to a large group of patients and then
measure the highest plasma drug concentration we would see that due to individual
variability, the resulting plasma drug concentrations differ. This variability can be
attributed to factors influencing drug absorption, distribution, metabolism, and
excretion. Therefore, drug dosage regimens must take into account any disease
altering state or physiological difference in the individual.
Therapeutic drug monitoring optimizes a patients drug therapy by determining
plasma drug concentrations to ensure the rapid and safe drug level in the therapeutic range.
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The major potential advantages of therapeutic drug monitoring are the maximization of therapeutic drug benefits and the minimization of toxic drug effects. The
formulation of drug therapy regimens by therapeutic drug monitoring involves a
process for reaching dosage decisions.
10.1.2
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10-4
hospital between the patients on gentamicin who were monitored (and their dosage
regulated as a consequence) vs. those who were not. With DRGs the hospital was
reimbursed a flat fee irrespective of the number of days the patient stayed in the
hospital. If the number of days cost less than what the DRG paid, the hospital
makes money. If the days cost more than the hospital loses money. This study
showed that if all patients in the hospital who were on gentamicin were monitored,
the hospital would save $4,000,000. Thats right FOUR MILLION per year. I
would say that would pay my salary, with a little left over, and that is only one
drug!
The process of
therapeutic monitoring
takes effort.
You must follow through to ensure proper changes have been made.
You must continue the process throughout therapy. Therapeutic monitoring, in many cases, will
be part of your practice. It can be very rewarding
Thus, if we have deterimined the therapeutic range, we could use pharmacokinetics to determine the optimum dosage regemin to maintain the patients plasma concentration within that range.
10.1.3
STEADY STATE
It is rare that a drug is given only once. Most therapies consist of multiple doses
of several days duration, if not several years. It is necessary, therefore, to be able
to asess plasma concenterations, both the peak which much be at or below the
MTC and the trough which must be at or above the MEC for the drug to be effective under these conditions. Thus when we dose a patient, the concentration profile must be within the Therapeutic Range during the entire time that the patient is
taking the drug. We can calculate the plasma concentrations in the followin manner. In the simplest model, suppose we give a drug by IV Bolus (because the math
is simpler). The equation which would result be
Cp = Cp 0 e
( kt )
D ( kt)
= ---- e
V
(EQ 10-1)
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10-5
(EQ 10-2)
1
D
Cp max = ---V
1
D ( ( k ) )
Cp min = ---- e
V
(EQ 10-3)
Upon giving a second dose, prior to the complete removal by the body of the first
dose the Cp max 2 would be the second dose plus what was left from the first dose:
2
D
D ( ( k ) )
Cp max = ---- + ---- e
V V
and the
Cp min
would be
Cp max
times
( ( k ) )
(EQ 10-4)
, thus:
2
( ( k ) )
( ( 2k ) )
: Cp min = D
---- e
+ D
---- e
Cp max
(EQ 10-5)
would be:
n
( ( k ) )
( ( ( n 1 ) k ) )
Cp max = D
---- + D
---- e
+ +D
---- e
V V
V
while the
Cp min
(EQ 10-6)
would be:
n
( ( k ) )
( ( 2k ) )
( ( nk ) )
Cp min = D
---- e
+ D
---- e
+ +D
---- e
V
V
V
(EQ 10-7)
Subtracting equation 10-7 from equation 10-6 to eliminate the series yields:
n
( nk )
n
D
D ( ( nk ) ) D
= ---- ( 1 e
)
Cp max Cp min = ---- ---- e
V
V
V
Cp min
is also
Cp max e
n
( k )
(EQ 10-8)
( k
= Cp max ( 1 e
( k )
Cp max
(EQ 10-9)
yields:
n
e
Cp max = D
---- 1---------------------------V 1 e( k )
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(EQ 10-10)
Cp max
ss
, is:
10-6
Cp max
ss
1
= D
---- ------------------------V 1 e( k )
Cp min
Cp min
ss
ss
(EQ 10-11)
, is :
( k
D
e
= ---- ------------------------V 1 e ( k )
(EQ 10-12)
In order to make a general equation set from equation 10-11 and equation 10-12,
let N be the number of half lives in a dosing interval,
k = ( ln ( 2 ) ) t 1 2
( k )
, yields
, and
N = --------t1 2
( k
N
= 1
---
2
and
ss
1 = D
---- -------------------V
1 N
1 ---
2
(EQ 10-13)
Cp min
ss
1
---
2
= D
---- --------------------V
1 N
1 ---
2
(EQ 10-14)
The average drug concentration under these conditions would be equivalant to the
steady state concentration attained by an infusion of the same rate, i.e. if we were
to give a multiple dose at 200 mg every four hours (q4h) or 400 mg every eight
hours (q8h), the average that would be attained would be equivelaent to the steady
state plasma concentration attained by giving an infusion at 50 mg/hr, (Q = 50 mg/
hr), and thus, in the infusion, the
k = 0.693 N
ss
Q
= ---------kV
D
Q = ---
, and
so:
Cp
Cp
ss
avg
D
D
1.443 D
= ------------------- = ------------------------------ = ---------------------V K V 0.693 N
NV
(EQ 10-15)
Similar equations, although more complex, can be derived for multiple dose oral
products. However, if we were agreed to live with some error these equations, with
some modifications could be used to approximate multiple dose oral products.
The error on both calculated Cp maxss and Cp minss would be in the direction of
safety, i.e. the calculated Cp maxss would be higher and the calculated Cp minss would
be lower that their respective multiple dose oral calculations. Thus, if the simpler
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10-7
equations place the Cp max ss and C minss within the Therapeutic Range, the oral multiple dose equations would also. The two modifications would be to the Dose. Bioavailability, f, must be considered, and if the drug given is not the drug measured in
the blood, the salt factor, S, the difference in the molecular weight of the two compounds must be taken into account, (i.e.
MW measured
S = -----------------------------MW given
for
using IV bolus equations as such :
Cp max
Cp
ss
avg
ss
SfD
1
= ------------------ --------------------N
V
1 1---
2
SfD
SfD
1.443 S f D
= ------------------- = ------------------------------ = -----------------------------------V K V 0.693 N
N V
Cp min
ss
1
---
2
(EQ 10-16)
(EQ 10-17)
S f D
= ------------------ --------------------V
1 N
1 ---
2
(EQ 10-18)
because errors involved with this approximation both in maximum and minimum
calculations (peak and trough) place the drug further within the Therapeutic
Range, i.e. the real peaks are lower than the calculated peaks and the real troughs
are higher than the calculated troughs, thus both errors are on the side of safety.
Dosing Interval
Cp max
N
MTC-----------= ------------------= 2 max
ss
MEC
Cp min
(EQ 10-19)
by deviding equation 10-18 into equation 10-16 and simplifying. Given these limits, the maximum dosing interval, max , is obtained by solving for Nmax:
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10-8
MTC-
Ln -----------MEC
= -------------------------Ln2
N max
and since
max
N max = ---------t1 2
(EQ 10-20)
by definition,
max
= N max t1 2
(EQ 10-21)
is not necessarily the dosing interval of choice, but it is the maximum dosing
interval attainable without sustained or controlled release delivery systems.
max
Accepable dosing intervals are those which result in a dose being given at the same
time of the day, every day. Imagine, if you will, the chaos on the nursing floor if
the dose for a given drug were every 15 hours. Compliance, none too high when
the patient is given a reasonable dosing interval, would go straight to the toilet if
we asked the patient to take a tablet every 5.3 hours. What would be optimal would
be to tie the takeing of the drug with an activity that occurs the same time every
day for once a day therapy, or at least dose the same time every day. Thus, for
multiple daily doses, the only regimens that work are those which when devide
into 24 hours give unit answers: QD = 24/1 = q24h; BID = 24/2 = q12h, TID = 24/
3 = q8h; QID = 24/4 = q6h; q4h; q3h; q2h. These result in decreasing orders of
patient compliance (unless the patient is really motivated to take the drug every 2
hours - forget it.) Thus the maximum acceptable dosing interval would be the largest acceptable dosing interval below the max . So, for example if max is 15.7
hours, the maximum acceptable dosing interval would be 12 hours. we could also
dose every 8, 6 or 4 hours if necessary.
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10-9
(EQ 10-22)
In general, if
changes in dosage regimen are not necessary. In order to return a previously controlled healthy pateint back to the therapeutic range, a general rule of thumb is suggested as an initial starting point. The desease modifies K (as t1/2) and V. As
pharmacists, we can modify D and . These variables are paired in the above
equations (equation 10-16 and equation 10-18), D with V (in
with
(in
N = --------t1 2
S----------------fD
V
) and
t1 2
would recommend a change in D proportionally, and if the half life changes, the
pharmacist would recommend a change in the dosing interval proportionally.
Remenber, the object is to get the plasma concentrations back to where they were
prior to the illness. The only problem is that we are limited to these recommended
changes being incremental and not continuous. That is a change in dose is limited
to the available dosage forms and strengths and a change in dosing interval is
limeted to the accepatable dosing interval.
Protein Binding
If the drug is highly protein bound, the object would be to get the free concentration back to what it was prior to illness. Consequently, equation 10-16, equation
10-17, and equation 10-18 would be rewritten thus:
Cp
Cp
ss
fu S f D
ss
1
= f u Cp
= ------------------------- -------------------N
V
max free
max
1 1---
2
ss
fu S f D fu S f D
ss
= fu C p
= -------------------------= -----------------------------VK
V 0.693 N
avg free
avg
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(EQ 10-23)
(EQ 10-24)
10-10
Cp
1
---
2
ss
fu S f D
ss
= fu Cp
= ------------------------- -------------------N
V
min free
min
1 1---
2
(EQ 10-25)
Some interesting and unexpected things result from these relationships. Since
plasma or blood concentrations are usually measured, if a drug is highly protein
bound and the desease results in upsetting that equilibrium, you might see toxicity
resulltling from normal or even subtherapeutic measured concentrations. More on
that in the chapter on protein binding.
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10-11
10.3 Problems
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10-12
Alprazolam
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 1)
AHFS 00:00.00
GPI: 0000000000
Juhl, R. et al., "Alprazolam pharmacokinetics in alcoholic liver disease", Journal of Clinical Pharmacology, Vol.24, (1984), p. 113
- 119.
Alprazolam is an anti-anxiety agent which is metabolized to 4-hydroxy and -hydroxy metabolites. In this
study, patients with cirrhosis of the liver and healthy patients were each given doses of 1.0 mg of Alprazolam. The following data is for healthy patients.
PROBLEM TABLE 10 - 1.
Alprazolam
Dose
1.0 mg BID
1.16 L/kg
1.22
529.3
AUC
Find k.
2.
3.
Find the .
4.
5.
Find .
6.
What is N?
7.
What is the patient's maximum plasma concentration, , under this dosage regimen.
8.
What is the patient's average plasma concentration, , under this dosage regimen.
9.
What is the patient's minimum plasma concentration, , under this dosage regimen.
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10-13
Cefixime
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 2)
AHFS 00:00.00
GPI: 0000000000
Faulkner, R. et al., "Pharmacokinetics of cefixime after once-a-day and twice-a-day dosing to steady state", Journal of Clinical
Pharmacology, Vol.27, (1987), p. 807 - 812.
Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram negative bacteria. In this study, patients received a 200 mg oral dose of cefixime twice daily.
PROBLEM TABLE 10 - 2.
Cefixime
Dose
200 mg BID
3.3 hours
286
32
AUC
14.12
1.
Find k.
2.
Find MRT.
3.
Find Cl.
4.
Find the .
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
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Cefpodoxime
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 3)
AHFS 00:00.00
GPI: 0000000000
Borin, M. et. al., "Pharmacokinetics and tolerance studies of cepodoxime after single-and multiple-dose oral administration of cefpodoxime proxetil", Journal of Clinical Pharmacology, Vol.31, (1991), p. 1137 - 1145.
Cefpodoxime proxetil is a third-generation, broad-spectrum cephalosporin which is given by the oral route. It is a prodrug which is converted in vivo to cefpodoxime which inhibits bacterial cell wall synthesis by binding to penicillinbinding proteins.
PROBLEM TABLE 10 - 3.
Cefpodoxime
Dose
100 mg BID
2.1 hours
271
79.1
AUC
6.9
1.
Find k.
2.
Find MRT.
3.
Find Cl.
4.
Find the .
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
10-15
Cefprozil
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 4)
AHFS 00:00.00
GPI: 0000000000
Lode, H. et. al., "Multiple-dose pharmacokinetics of cefprozil and its impact on intestinal flora of volunteers", Antimicrobial
Agents and Chemotherapy, Vol.36, (1992), p. 144 - 149.
Cefprozil is a broad-spectrum cephalosporin which is given by the oral route. In this study subjects received 500 mg
doses of cefprozil every twelve hours for eight days.
PROBLEM TABLE 10 - 4.
Cefprozil
Dose
500 mg q. 12 hours
55.11minutes
310.25
277.50
AUC
27.80
1.
Find k.
2.
Find MRT.
3.
Find Cl.
4.
Find the .
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
10-16
Clobazam
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 5)
AHFS 00:00.00
GPI: 0000000000
Greenblatt, D. et. al., "Reduced single-dose clearance of clobazam in elderly men predicts increased multiple-dose accumulation",
Clinical Pharmacokinetics, Vol.8, (1983), p. 83 - 94.
Clobazam is an agent used in the treatment of anxiety. In this study, patients received 10 mg dose of clobazam daily.
PROBLEM TABLE 10 - 5. Clobazam
Dose
10 mg daily
180 hours
AUC
1.
Find k.
2.
Find MRT.
3.
Find the ?
4.
5.
Find .
6.
What is N?
7.
What is the patient's maximum plasma concentration, , under this dosage regimen.
8.
What is the patient's average plasma concentration, , under this dosage regimen.
9.
What is the patient's minimum plasma concentration, , under this dosage regimen.
10.
Your patients renal function drops to 50% of normal. What would be a new dosing regimen under these conditions? (Assume that you want to keep < 110% of the normal and that you want to keep > 90% of the normal .)
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
10-17
Maloprim
(Problem 10 - 6)
AHFS 00:00.00
GPI: 0000000000
Edstein, M., Rieckmann, K., and Veenendaal, J., "Multiple-dose pharmacokinetics and in vitro antimalarial activity of dapsone
plus pyrimethamine (Maloprim ) in man", British Journal of Clinical Pharmacokinetics, Vol.30, (1990), p.259 - 265.
Maloprim is an agent which contains both dapsone and pyrimethamine. In this study, healthy volunteers
were given 100 mg of dapsone plus 12.5 mg pyrimethamine weekly. The following data is for dapsone:
PROBLEM TABLE 10 - 6. Maloprim
Dose
100 mg weekly
22.6 hours
AUC
35.0
1.
Find k.
2.
Find MRT.
3.
Find Cl.
4.
Find the .
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-18
Doxycycline
(Problem 10 - 7)
AHFS 00:00.00
GPI: 0000000000
Shmuklarsky, M. et. al., "Failure of doxycycline as a causal prophylactic agent against Plasmodium falciparum malaria in healthy
nonimmune volunteers", Annals of Internal Medicine, Vol.120, (1994), p. 294 - 298.
Doxycycline is an antibiotic which has been recommended for prevention of malaria in people traveling to areas
endemic to chloroquine-resistant P. falciparum malaria who are unable to take mefloquine. This study determined that
doxycycline is not effective for this use. Volunteers were given 100 mg doses of doxycycline daily for 10 days.
PROBLEM TABLE 10 - 7.
Doxycycline
Dose
100 mg daily
21.9 hours
AUC
40.7
1.
Find k.
2.
Find MRT.
3.
Find Cl.
4.
Find the .
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-19
DQ-2556
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 8)
AHFS 00:00.00
GPI: 0000000000
Nakashima, M. et. al., "Phase I study of DQ-2556, a new parenteral 3-quaternary ammonium cephalosporin antibiotic", Journal of
Clinical Pharmacology, Vol.33, (1993), p. 57 - 62.
DQ-2556 is a new broad-spectrum cephalosporin which is active against many bacteria including Pseudomonas aeruginosa. Subjects in this study were each given a 2000 mg infusion of DQ-2556 over 5 minutes every 12 hours for a total
of 9 doses.
PROBLEM TABLE 10 - 8.
DQ-2556
Dose
AUC
241.0
1.
Find Cl.
2.
Find k.
3.
4.
Find the .
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-20
Erythropoetin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 9)
AHFS 00:00.00
GPI: 0000000000
Gladziwa, U., et al., "Pharmacokinetics of epoetin (recombinant human erythropoietin) after long term therapy in patients undergoing haemodialysis and haemofiltration", Clinical Pharmacokinetics, Vol.8, (1983), p. 83 - 94.
Erythropoetin is a regulatory hormone of red blood cells. In this study patients with end-stage renal disease were given
150 U/kg of epoetin three times a week.
PROBLEM TABLE 10 - 9.
Glipizide
Dose
Cl
5.4
Assuming that your patient weighs 65 kg, please determine the following:
1.
Find k.
2.
Find MRT.
3.
Find the .
4.
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-21
Flecainide
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 10)
AHFS 00:00.00
GPI: 0000000000
Forland, S. et al., "Flecainide pharmacokinetics after multiple-dosing in patients with impaired renal function", Journal of Clinical
Pharmacology, Vol.28, (1988), p. 727 - 735.
Flecainide acetate is a class 1C anti-arrhythmic agent which is used in the treatment of ventricular and supraventricular
arrhythmias. In this study, subjects were given doses of 100mg of flecainide orally twice daily.
PROBLEM TABLE 10 - 10. Flecainide
Dose
100 mg BID
7.4 L/kg
486
89
AUC
3.429
Find Cl.
2.
Find k.
3.
4.
Find the .
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-22
Glipizide
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 11)
AHFS 00:00.00
GPI: 0000000000
Kradjan, W. et al., "Glipizide pharmacokinetics: effects of age, diabetes, and multiple dosing", Journal of Clinical Pharmacology,
Vol.29, (1989), p. 1121 - 1127.
Glipizide is a second-generation oral hypoglycemic agent used in the treatment of non-insulin-dependent (type II) diabetes. In this study, both diabetic and non-diabetic elderly men were each given doses of 2.5 mg of glipizide daily for
five days. The data for the non-diabetic group is given below.
PROBLEM TABLE 10 - 11.
Dose
2.5 mg daily
4.0 hours
0.47
AUC
2325.4
1.
Find k.
2.
Find MRT.
3.
Find Cl.
4.
Find the .
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-23
Lomefloxacin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 12)
AHFS 00:00.00
GPI: 0000000000
Hunt, T. and Adams, M., "Pharmacokinetics and safety of lomefloxacin following multiple doses", Diagn Microbiol Infect Dis,
Vol.12, (1989), p. 181 - 187.
Lomefloxacin is a quinolone antibiotic which is useful against both Gram-positive and Gram-negative bacteria. It is
used in the treatment of urinary tract infections and lower respiratory tract infections. A dose of 400 mg of lomefloxacin was given twice daily to healthy patients.
PROBLEM TABLE 10 - 12. Lomefloxacin
Dose
400 mg BID
7.32 hours
AUC
61.67
1.
Find k.
2.
Find MRT.
3.
Find Cl.
4.
Find the .
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-24
Loratadine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 13)
AHFS 00:00.00
GPI: 0000000000
Radwanski, E. et al., "Loratadine: multiple-dose pharmacokinetics", Journal of Clinical Pharmacology, Vol.27, (1987), p. 530 533.
Loratadine is an antihistamine which is orally active. In this study, healthy, male volunteers were each given a 40-mg
loratadine capsule daily for ten days.
PROBLEM TABLE 10 - 13. Loratadine
Dose
40 mg daily
14.4 hours
AUC
96.0
1.
Find k.
2.
Find MRT.
3.
Find Cl.
4.
Find the .
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-25
Methamphetamine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 14)
AHFS 00:00.00
GPI: 0000000000
Cook, C., et al., "Pharmacokinetics of oral methamphetamine and effects of repeated daily dosing in humans", Drug Metabolism
and Disposition, Vol.20, (1992), p. 856 - 861.
Methamphetamine is a CNS stimulant which is used in the treatment of attention deficit disorder and obesity. In this
study, subjects were given a 0.125 mg/kg dose of methamphetamine daily.
PROBLEM TABLE 10 - 14. Methamphetamine
Dose
Find k.
2.
Find MRT.
3.
Find the .
4.
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-26
Mexiletine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 15)
AHFS 00:00.00
GPI: 0000000000
Gillis, A. and Kates, R., "Clinical pharmacokinetics of the newer antiarrhythmic agents", Clinical Pharmacokinetics, Vol.9, (1984),
p. 375 - 403.
Mexiletine is a class Ib antiarrhythmic agent. In this study, volunteers each received a 1600 mg dose orally each day.
PROBLEM TABLE 10 - 15. Mexiletine
Dose
1600 mg daily
380 L
681
1.
Find k.
2.
3.
Find the .
4.
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-27
Moxisylyte
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 16)
AHFS 00:00.00
GPI: 0000000000
Costa, P. et al., "Multiple-dose pharmacokinetics of moxisylyte after oral administration to healthy volunteers", Journal of Pharmaceutical Sciences, Vol.82, (1993), p. 968 - 971.
Moxisylyte is an -adrenergic blocker which has been used in Europe for some times as a vasodilator in the
treatment of such disease states as age-associated mental impairment, acrocyanosis, Raynaud's syndrome, vascular cochlearvestibular disorders, glaucoma, and benign prostatic hyperplasia.
PROBLEM TABLE 10 - 16. Moxisylyte
Dose
240 mg BID
2.28 hours
AUC
11186
1.
Find k.
2.
Find MRT.
3.
Find Cl.
4.
Find the .
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
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10-28
Naproxen
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 17)
AHFS 00:00.00
GPI: 0000000000
Ouweland, F. et. al., "Hypoalbuminaemia and naproxen pharmacokinetics in a patient with rheumatoid arthritis", Clinical Pharmacokinetics, Vol.11, (1986), p. 511 - 515.
The pharmacokinetics parameters of naproxen were looked at in patients with rheumatoid arthritis in this study. A
patient received a dose of 500 mg of naproxen orally twice daily.
PROBLEM TABLE 10 - 17. Naproxen
Dose
500 mg BID
9.0 L
AUC
1134
1.
Find Cl.
2.
Find k.
3.
4.
Find the .
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-29
Nisoldipine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 18)
AHFS 00:00.00
GPI: 0000000000
Harten, J. et al., "Influence of renal function on the pharmacokinetics and cardiovascular effects of nisoldipine after single and
multiple dosing", Clinical Pharmacokinetics, Vol.16, (1989), p. 55 - 64.
Nisoldipine is a second-generation calcium-channel blocker which is under investigation for use as an anti-hypertensive agent. Nisoldipine is mainly eliminated through liver metabolism with metabolites being excreted mainly in the
urine but also in the feces. The systemic clearance of nisoldipine depends greatly on liver blood flow.
PROBLEM TABLE 10 - 18. Nisoldipine
Dose
10 mg BID orally
7.9 hours
AUC
5.2
1.
Find k.
2.
Find MRT.
3.
Find Cl.
4.
Find the ?
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-30
Pefloxacin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 19)
AHFS 00:00.00
GPI: 0000000000
Bruno, D. et al., "Bayesian versus NONMEM estimation", , Vol. , (19 ), p. 657 - 668.
Pefloxacin is an antibiotic used to treat patients who are in the intensive care unit. For this study, patients were given a
400 mg dose of pefloxacin twice daily for eight days.
PROBLEM TABLE 10 - 19. Pefloxacin
Dose
400 mg BID
21.3 hours
Cl
3.77
1.
Find k.
2.
Find MRT.
3.
Find the ?
4.
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-31
Phenylpropanolamine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 20)
AHFS 00:00.00
GPI: 0000000000
Scherzinger, S., Rowse, R., and Kanfer, I., "Steady state pharmacokinetics and dose-proportionality of phenylpropanolamine in
healthy subjects", Journal of Clinical Pharmacology, Vol.30, (1990), p. 372 - 377.
Phenylpropanolamine is a sympathomimetic agent which is used both for its action as a nasal decongestant and its
action as an anorexiant. In this study healthy volunteers were given doses of 25 mg every four hours for a total of
seven doses. It was found that phenylpropanolamine is 77% renally excreted.
PROBLEM TABLE 10 - 20. Phenylpropanolamine
Dose
25 mg q. 4 hours
4.71 hours
4.08 L/kg
0.5
1.
Find k.
2.
Find MRT.
3.
Find Cl.
4.
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-32
Promethazine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 21)
AHFS 00:00.00
GPI: 0000000000
Taylor, G. and Houston, J., "Changes in the disposition of promethazine during multiple dosing in rabbits", Journal of Clinical
Pharmacology, Vol.37, (1985), p. 243 - 247.
Promethazine is an agent used as an anti-histamine and a sedative. In this study rabbits weighing 2.7 to 3.3 kilograms
each received a 10 mg/kg dose of promethazine every 24 hours for 14 days.
PROBLEM TABLE 10 - 21. Promethazine
Dose
10 mg/kg
249 minutes
65.0
1.
Find k.
2.
Find MRT.
3.
Find the ?
4.
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-33
Rufloxacin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 10 - 22)
AHFS 00:00.00
GPI: 0000000000
Mattina, R. et al., "Pharmacokinetics of rufloxacin in healthy volunteers after repeated oral doses", Chemotherapy, Vol.37, (1991),
p. 389 - 397.
Rufloxacin is a broad-spectrum, fluoroquinolone antibiotic. In this study a patient was given a loading dose of 300 mg
of rufloxacin followed by 150 mg of rufloxacin daily for five days.
PROBLEM TABLE 10 - 22. Rufloxacin
Dose
150 mg daily
104 L
41
10
AUC
121.5
1.
Find k.
2.
3.
Find the .
4.
5.
Find .
6.
What is N?
7.
What is the patient's maximum plasma concentration, , under this dosage regimen.
8.
What is the patient's average plasma concentration, , under this dosage regimen.
9.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-34
(Problem 10 - 23)
AHFS 00:00.00
GPI: 0000000000
Puri, S. et al., "Multiple dose pharmacokinetics, safety, and tolerance of velnacrine (HP 029) in healthy elderly subjects: a potential therapeutic agent for Alzheimer's disease", Journal of Clinical Pharmacology, Vol.30, (1990), p. 948 - 955.
Velnacrine is an investigative agent which has central cholinergic action and may be beneficial in the treatment of
Alzheimer's disease. Healthy, elderly, men were given doses of 100 mg twice daily in this study. It was found that 30%
of the velnacrine dose was excreted unchanged.
PROBLEM TABLE 10 - 23. Velnacrine
Dose
(HP 029)
100 mg BID
2.4 hours
AUC
809.5
1.
Find k.
2.
3.
Find Cl.
4.
Find the .
5.
6.
Find .
7.
What is N?
8.
What is the patient's maximum plasma concentration, , under this dosage regimen.
9.
What is the patient's average plasma concentration, , under this dosage regimen.
10.
What is the patient's minimum plasma concentration, , under this dosage regimen.
Basic Pharmacokinetics
REV. 99.4.25
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10-35
10.4 Answers
Alprazolam
1.
0.0631 h-1
2.
15.85 hours
3.
10.98 hours
4.
8387.81
5.
12
6.
1.093
7.
23.19
8.
16.26
9.
10.876
Cefixime
1.
0.210 h-1
2.
4.76 hours
3.
14.164 L/h
4.
67.435 L
5.
62.224
6.
12
7.
3.64
8.
3.225
9.
1.177
10.
0.259
Cefpodoxime
1.
0.330 h-1
2.
3.03 hours
3.
14.49 L/h
4.
43.91 L
5.
20.905
Basic Pharmacokinetics
REV. 99.4.25
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10-36
6.
12
7.
5.714
8.
2.322
9.
0.575
10.
0.0442
Cefprozil
1.
0.0126 min-1
2.
76.51 minutes
3.
17.99 L/h
4.
23.83 L
5.
36.84
6.
12
7.
13.065
8.
20.98
9.
2.317
10.
2.45
Maloprim
1.
0.0307 h-1
2.
32.6 hours
3.
2.857 L/h
4.
93.16 L
5.
1141.17
6.
168
7.
7.435
8.
1.08
9.
0.208
10.
6.25
Doxycycline
1.
0.0317 h-1
Basic Pharmacokinetics
REV. 99.4.25
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10-37
2.
31.595 hours
3.
2.457 L/h
4.
77.629 L
5.
1285.92
6.
24
7.
1.096
8.
2.42
9.
1.696
10.
1.133
DQ-2556
1.
8.299 L/h
2.
0.4715 h-1
3.
2.12 hours
4.
1.47 hours
5.
511.11
6.
12
7.
8.163
8.
114
9.
20.083
10.
0.398
Erythropoetin
1.
0.09 h-1
2.
11.11 hours
3.
3599.24 mL
4.
30092.6
5.
334291.14
6.
72
7.
9.35
8.
2713.24
Basic Pharmacokinetics
REV. 99.4.25
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10-38
9.
417.98
10.
4.156
Glipizide
1.
0.173 h-1
2.
5.77 hours
3.
1.075 L/h
4.
6.204 L
5.
13419.37
6.
24
7.
8.
0.4094
9.
96.893
10.
6.396
Flecainide
1.
29.16 L/h
2.
0.0563 h-1
3.
17.76 hours
4.
12.31 hours
5.
60.91
6.
12
7.
0.975
8.
0.393
9.
0.286
10.
0.200
Lomefloxacin
1.
0.0947 h-1
2.
10.56 hours
3.
6.486 L/h
4.
68.497 L
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10-39
5.
651.27
6.
12
7.
1.639
8.
8.6
9.
5.139
10.
2.76
Loratadine
1.
0.0481 h-1
2.
20.77 hours
3.
416.67 L/h
4.
8656.17 L
5.
1994.38
6.
24
7.
1.67
8.
6.746
9.
10.
2.125
Methamphetamine
1.
0.082 h-1
2.
12.21 hours
3.
46.7 L
4.
2.244
5.
27.383
6.
24
7.
2.837
8.
213.74
9.
93.48
10.
29
Moxisylyte
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10-40
1.
0.304 h-1
2.
3.29 hours
3.
0.0215 L/h
4.
70.574 mL
5.
36794.61
6.
12
7.
5.263
8.
3.492
9.
0.9322
10.
0.0909
Naproxen
1.
0.441 L/h
2.
0.049 h-1
3.
20.412 hours
4.
14.149 hours
5.
23147.21
6.
12
7.
0.848
8.
124.98
9.
94.5
10.
69.43
Mexiletine
1.
0.1075 h-1
2.
9.3 hours
3.
6.45 hours
4.
39.16
5.
364.17
6.
24
7.
3.723
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10-41
8.
4.256
9.
1.632
10.
0.345
Nisoldipine
1.
0.0877 h-1
2.
11.397 hours
3.
1923.08 L/h
4.
21.92 mL
5.
59.27
6.
12
7.
1.52
8.
700.7
9.
433.3
10.
244.5
Pefloxacin
1.
0.0325 h-1
2.
30.73 hours
3.
115.85 L
4.
106.1
5.
3260.4
6.
12
7.
0.563
8.
10.68
9.
8.84
10.
7.23
Phenylpropanolamine
1.
0.147 h-1
2.
6.795 hours
3.
36.03 L/h
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10-42
4.
0.694
5.
4.715
6.
7.
0.849
8.
229.5
9.
173.5
10.
127.4
Promethazine
1.
0.167 h-1
2.
5.987 hours
3.
70.05 L
4.
2.56
5.
15.35
6.
24
7.
5.78
8.
436.19
9.
106.84
10.
7.92
Rufloxacin
0.0237 h-1
42.28 hours
29.30 hours
5136.6
24
0.819
3.33
2.54
1.89
Velnacrine
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10-43
1.
0.289 h-1
2.
3.462 hours
3.
123.53 L/h
4.
427.73 L
5.
2802.87
6.
12
7.
8.
241.33
9.
67.46
10.
7.54
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CHAPTER 11
Multicompartment Modeling
OBJECTIVES
1.
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Multicompartment Modeling
11.2 Equations
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Multicompartment Modeling
For many drugs the equilibrium between drug concentrations in different tissues is
not achieved rapidly. Thus, one of the assumptions of the one-compartment open
model sometimes becomes invalid. A more complex mammillary open model is
often necessary to describe mathematically the plasma concentration data (for
example) seen after the administration of some drugs. The simplest mammillary
open model is a two-compartment open model: for example:
Compartment One (central compartment) can be sampled through the blood (or
plasma, or serum). It may consist of organs or tissues which, being highly perfused
with blood, are in rapid equilibrium distribution with the blood.
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On semilogarithmic paper the terminal phase is linear, indicating that initial distribution has been completed and that equilibrium has been attained. The terminal
half-life ( t 1 2 ) can be measured from the terminal phase.
Cp = ( Cp )o e
kt
(EQ 10-26)
i.e., the concentration of drug in the plasma declines exponentially with time
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Multicompartment Modeling
Cp = ( A1 e
+ B1 e
(EQ 10-27)
i.e., the concentration of drug in the plasma declines biexponentially with time
2.1 Symbols
(L )
= 0.5 [ ( k 10 + k 12 + k 21 ) + ( k 10 + k 12 + k 21 ) 4k 10k 12 ]
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Multicompartment Modeling
= 0.5 [ ( k 10 + k 12 + k 21 ) ( k 10 + k 12 + k 21 ) 4k 10k 12 ]
D- ( k 21 )
A 1 = ---- ---------------------V1 ( )
( k 21 )
D- --------------------B 1 = ----V1 ( )
A 1 + B1 = ( Cp ) o
(EQ 10-28)
c. Calculate the terminal hybrid rate constant ( ) ; in reality it contains both distributive ( k 12 and k 21 ) and elimination ( k 10 ) factors.
0.693
= ------------t1 2
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(EQ 10-29)
11-7
Multicompartment Modeling
d. Draw a straight line through the linear terminal elimination phase and extralpolate this line to t = 0. The intercept is equal to B1 .
( C p )diff = C p C p
g. Plot ( C p )diff against t (see Eq.8) on semilogarithmic paper. The is a feathered line and should decline linearly.
h. Find the half-life of the plot. It wil refer to the initial phase. Calculate,
i. Measure the intercept of the feathered line; it will equal to A 1 (Note that usually A1 = B1 , even theoetically).
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Multicompartment Modeling
k. Calcultate V1 by
Xo
D
= -----------------V1 = ------------( Cp )o A1 + B 1
(EQ 10-30)
.
Theory
When t is large, e
<e
Cp = B1 e
(EQ 10-31)
i.e., when t is large, the concentration of the drug in the plasma declines exponentilly with time.
(EQ 10-32)
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Multicompartment Modeling
( C p ) diff = A 1 e
(EQ 10-33)
i.e., the difference between observed and extrapolated drug concentrations in the
plasma declines exponentially with time.
Note (for reference only)
It is usually not informative to determine the microrate constant; but see one use
under the note on dosage regimens.
B 1 + A1
k 21 = ------------------------A 1 + B1
k 10 = k 21
k 12 = + k 10 k 21
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Multicompartment Modeling
D Cl = ---------------------
( AUC )o
(EQ 10-34)
b. The volume terms are complex than in a one-compartment open model. There
are two terms of interest:
This volume may be defined only in relation to the terminal phase ( phase), when
initial distribution has been completed.
D
V = -------------------------
( AUC )o
As V requires calculation of the total area under the plasma concentration against
time curve it is sometimes known as Varea .
Cl = V
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(EQ 10-35)
11-11
Multicompartment Modeling
Cl = k 10V 1
(EQ 10-36)
This follows as systemic clearance is always given by the elimination rate constant
out of the body multiplied by the apparent volume of distribution in the compartment from which drug leaves the body. Comparing Eqs. 11 and 12,
k 10
V = ------V
1
(EQ 10-37)
Note that k 10 (the elimination rate constant) is not the same as (the terminal
hybrid rate constant).
2.5 Bioavailability
Find ( AUC )0 using trapezoidal rule and, if necessary, the calculation for the terminal area.
t C
( AUC )o = ( AUC )o + -----p
(EQ 10-38)
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Multicompartment Modeling
D = ( C p ) ss Cl
The loading dose ( D L ) achieves a steady-state condition quite rapidly, but only
after initial distribution has been completed. It is given by the previous equation.
D
D L = -------------------------- 0.693N
1e
(EQ 10-39)
As may be expected, equations relating ( C max )ss and ( C min ) ss to ( C p )ss are as
before,
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Multicompartment Modeling
- 1 + k-----12
------ = 1
k 10
k 21
This is why, despite the fact that an open two-compartment model is better description of the pharmacokinetic of these drugs, a simple open-compartment model may
often be assumed for dosage regimen purposes.
X2 = B2 ( e
(EQ 10-40)
k 12D
Where B2 = ----------------( )
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Multicompartment Modeling
Note that the equations forms bears a similarity to that seen for plasma concentrations after oral administration inot a one compartment open model.
When t is large, e
<e
X2= B2 e
(EQ 10-41)
(EQ 10-42)
Thus, when t is large the masses of drug in each compartment decline exponentially, and in parallel, with time. This indicates that initial distribution has been
completed and equilibrium attained.
If the value of X 2 reflects drug concentrations at the active site, the time of maximum concentration (and maximum pharmacological effect) is:
ln ( )
t max = --------------------
(EQ 10-43)
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Multicompartment Modeling
At a time just after t max the plasma concentration may exhibit a nose, when
compared to the profile of an open one-compartment model.
SELECTED REFERENCES
Riegelmen, S., Loo, J.C.k., and Rowland, M., Concept of a volume of distribution
and possible errors in evaluation of this parameter, J. Pharm. Sci., 57, 128-133
(l968).
Benet, L.Z. and Ronfeld, R.A., Volume terms in pharnacokinetics, J. Pharm. Sci.,
58, 639-641 (l969).
Gibaldi, M Nagashima, R., ant Levy, G., Relationship between drug concentrations in plasma or serum and amount of drug in the body, J. Pharm. Sci., 58, 193197 (1969).
Basic Pharmacokinetics
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Gibaldi, M. and Perrier, D., Drug eliminatin and apparent volume of distribution in
multicompartment systems, J. Pharm. Sci., 61, 952-954 (1972).
Gillette, J.R., The importance of tissue distribution in pharmacokinetics, J. Pharmacokinetics. Biopharm., 1, 497-520 (1973).
As apparent volumes of distribution are proportionality constants, and not physiological volumes, more than one term is of value.
This relates the concentration of drug in the sampled compartment with the mass
of drug present in that compartment.
D
V1 = --------------------------
K ( AUC )o
(EQ 10-44)
(EQ 10-45)
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(EQ 10-46)
11-17
Multicompartment Modeling
This volume term (sometimes known as the apparent volume of distribution of the
drug in the body) requires the assumption that the drug is evenly distributed
throughout the body. The assumption is not true in practice. Thus V can only be
defined in relation to the terminal phase ( -phase) when equilibrium has been
attained; the equation is analogous to Eq. 2.
D
V = -------------------------
( AUC )o
(EQ 10-47)
(EQ 10-48)
Cl m = k m V1
(EQ 10-49)
Cl s = KV 1
(EQ 10-50)
(EQ 10-51)
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Multicompartment Modeling
Cl s = V
(EQ 10-52)
K
V = ---V
1
(EQ 10-53)
Selected References
Riegelman, S., Loo, J.C.K., and Rowland, M., Concept of a volume of distribution
and possible errors in evaluation of this parameter, J. Pharm. Sci., 57, 128-133
(1968).
Benet, L.Z. and Ronfeld, R.A., Volume terms in pharmacokinetics, J. Pharm. Sci.,
58, 639-641 (1969).
Gibaldi, M., Nagashima, R., and Levy, G., Relationship between drug concentrations in plasma or serum and amount of drug in the body, J. Pharm. Sci., 58, 193197 (1969).
Perrier, D. and Gibaldi, M., Relationship between plasma or serum drug concentration and amount of drug in the body at steady state upon multiple dosing, J. Pharmacokin. Biopharm., 1, 17-22 (1973).
Oie, S. and Tozer, T.N., Effect of altered plasma protein binding on apparent volume of distribution, J. Pharm. Sci., 68, 1203-1205 (19793).
Li;vxrX LLrLLxLS
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Multicompartment Modeling
As,l
(in)(dS 1)
2 InDut Functions
.
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Multicompartment Modeling
2.1 IV Bolus
(in) - D
where D is the dose
2.2 IV Infusion
Q (l-e sb)
where Q is the zero-order infusion rate, b-t when e<T, b-T when eiT, and T is the
eime of cessation of infusion.
(in) . <
(s+ka)
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Multicompartment Modeling
(s+kr) (s+ka)
(la)
ka(l-e sb)
s(s+k>)
2-6 Others
These may be formed by adtition of functions 2-1 through 2-5
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Multicompartment Modeling
is Ei.
As,~
n~
kca
a +
where q is the compartment into which input occurs, n is the number of driving
force compartments,
kql is the first-order rate constant for transfer of drug from input compartment eo
compartment one,
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Multicompartment Modeling
kl; and kjl are the first-order rate constants for drug transfer from compartment 1 to
compartment j, ant vice-versa.
(b) Tr (Pi) and fT (Pm) are coneinued produces. ~e value of Pi (or Pm) equals one
when thc counter i (or m) takes on a forbidden number. For example, i-l is forbidden in the numerator, ant m-l and m-j are forbidden in the denominaeor. 3-Z
E.camples
ds,l = 1
(Eq.l)
ds , 1
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Multicompartment Modeling
dS,l
k21 (s+E3)
(Eq.2)
(Eq.3)
3-3 Simplifying the Denominator The number of exponeneial terms in ehe final
ineegrated equation will be equal eo the number of driving force compartments
(n). This is also equal to the maximum power to which the Laplace operator (s)
would nppear if
(a) ds,l
(b) d5 l
(c)
ts.l
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Multicompartment Modeling
(s+kl)
(s+E2)
(s+kl) ts I k2)
k21 (s+E3)
(Eq.la)
(Eq.2a)
(Eq.3a)
The exact meaning of [i for any model depends on the equalities evident in the
denominaeors. Example for (b):
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Multicompartment Modeling
( s+kl ) ( S+k2 )
(b) Cover the factor with a finger, and remember its root.
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Multicompartment Modeling
(c) Wherever the Laplace operator(s) occurs in the uncovered transform, subseitute
the root for s.
(d) Multiply the resule by eses again substituting ehe rooe for s
(e) After doing (b) through (d) for each factor, simplify.
Example:
X1 D(-kl+E2)e-klt - + D(-k2+E2)e~k2t
(-kl+k2)(-k7+kl )
or C1 - D (kl-Ez)e kl + D (E2-k2)e 2
V1 (kl k2 )
or
C1 - Ale 1 + A2e-k2t
In this example the meaning of A1, A2, kl, k2, and E2 depend on the form
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Multicompartment Modeling
(b) Take the Laplace Transform of each side of the differential rate equation, using
the table where necessary.
V1 (kl-k2)
(t) Substitute for anv known transformed dependent variables on tlle right-lland
sidc of the equation.
(e) Solve (integrate) bv the method of partial fractions (tlle hidden 1land), and
simplifv.
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Multicompartment Modeling
52(5+kl) (s+k2)
where klo is the first-order excretion rate constant from compartment one.
xu ~ kloQ.E2b + ......
klk2
Xu t kloQ- E2Elb I
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Multicompartment Modeling
klk2k3
REFERENCES
L.Z. Benet, General treatment of linear mammillary models with elimination from
any compartment as used in pharmacokinetics, J. Pharm. Sci., 61, 536-541 (1972)
D.P. Vaughan, D.J.H. Mallard, A. Trainor, and M. Mitchard, General pharmacokinetic equations for linear mammillary models with trug absorption into peripheral
compartments, Europ. J. Clin. Pharmacol., 8, 141-148 (1975).
D.P. Vaughan and A. Trainor, Derivation of general equations for linear mammillary models when ehe drug is administered by different routes, J. Pharmacokin.
Biopharm., 3, 203-218 (1975).
Two-Compartment Model-l
Prior inputs focuset on one-compartmcnt models, but many drugs arc charactetizet
bettcr by multicompartmcnt motek. In the following three inputs, we shall bricfly
tiscuss multico~_nt motek ant prcstnt a few apB plicadons. Multicompartnent motcis are not uset as fo quentlg u the one-compartment model in therapeutic trug
monitonng, panly because they arc more tifficult to construct ant apply.
Gencially, muldeaw models arc appliet when th,e natural log of plasma drug consentration vcrsus time is not lincar afier an intravenous tose or when thc plasma
concentration versus time psfilc cannot bc chu~ by a single cxpooential function
(i.c., C, - CO e~~). Wben the In of plasma concentration vcrsus timc is not a
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Multicompartment Modeling
Of the mul
models, tbe two-compartment motel is tnost fxqucntly uset. lunis model usually
of thc weU-perfia
tissues ant penpbexal compartment of less weU Erfuset dssues (such as muscle
ant fat). hgure 23^ shows a diagram of thc two-compartmcnt model afir an intravenous bolus tose, where:
consists of a central
K,2rate const nt for transfcr of drug from cd-compartment zo petipheral compartment rne subsaipt 12 irldicses tr nsfcr from thc first (cd) to the second
(peripheral) compattments.
K2, - rate constant for tgansfcr of drugfrov peripheral computment to central comp
rtment lbe subscript 21 indicales tr nsfcr from Ulc second (periphaal) to the fint
Xo~
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Kl2
K2l
+ Klo
fintvder climinX aue consunt (similar to tbe Jr uxd paviously), iting elimiXn of
dmg out of tbe caul ~ into urine, feces,
esc~
A log plasma conscatration versus time curve for a two-compattment model shows
a curvilinear profilea atrved potoon followed by a straight li=. This biexponential curve c n bc described by two expoKntial tcrms (Flgure 23B). lEc phases of
the curve may reprcstnt rapid d1stributioo to organs with high blood flow (central
compuenent) and slower distnbution to organs with Ess blood flow (penphcnl
compartmcnt).
Mer thc intovenous injection of a drug that follows a t_ model, thc drug consentrations in all fluids and dmms associated with tbc central compartmcnt declinc morc
rapidly in tbc distributioo phasc thao during the post-diwibubon phasc. ARcr sornc
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For many drugs, suco as aminoglycosides, thc distributdoo phast is vcry shott (e.g.,
1920 mtn). If serum consentradons are measured after this phase is compited, toe
ceotral compartmcot can be ignorcd and a one-compartrKnt model adequatcly
repttsents the serum coocentratioos observed. However, for drugs such as vancomycin, thc-distribution phase lasts 1-2 hr after an intravenous dosc. If plasma concentrations of vancomycin are determined within the first hour after a dose is
given, thc nonlincar (multiexponential) decline of vancomycin concentrations
must bc considered.
REVIEW PROBLEMS
23.2. The log plasms concentration vcrsus time curve for a two-compartment
model is reprcsented by a (bicxponential or monoexponential) cuNe. (Sclect one.)
23.3. The first portion of the log plasma concentration ver. sus timc cune. where
the log concentration r;tpidly declincs. is lomwn as the
phasc.
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11- 1
~1
I>Pur 2t 61
70 [ So
~i
~m
~.
F*wf 238 Four st ges of drug distribution nd eliminatioo following rapid intravenous injectiott. Points I, U, m, nd tv (ript) corrcspond to the points oo the plasmx
concentntion curve (leR). Point 1: The injection has just becn compicted, and drug
density io the cd compartment is hipcst. Drug distribution and elimination hve just
begun. Poin~ 11: At midway through tbe distributioo process, the drug density in
thc central compartment is falling r pidly, dulioly owing to rapid drug distributioo
out of the centd ccrnpartment into the peripheral compartment. The density of drug
io the peripheral compartment has not yet mched tht in the central compartmcnt.
Poixt 111: Distribution equilibrium h s been attained, and drug densitics in the
centd and periphed compartments arc appgoximately equal. Drug distribution in
both directioos contioucs to talze place, but the ratio of drug quantitics in toe centel
and peripheral compartments remains constant. At this point, the major determinant of drug disappearance from thc central compartmcnt becomes the elimination
process; previously, drug disappearance W&S determined mainly by distribution.
Poi/s : During this elimination phase, the drug is being -drained from both com-
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Multicompartment Modeling
partmcnts out of the body (via the central companment) at approximatcly the same
rate. (Reproduced, with permission, from Grecnblatt DJ &nd Shader Rl, Phrmacolsinetics in clinical practice, W.B. Saunders, Philadelphia. PA, 198S.)
TwoW M~
horo tiscussioo of the ooe-comparaneot model, we koow that the climination zte
coostant (J[) is estsmated fxm the slope of the lo pbsma coocentration vcrsus ame
curve. However, in a two-canzrg tnodel, wose the lo plasma coocentration versus
time curve is curvilinear, the slope varics, tepcndiog on waich porioo of toe curve
is cxamined (Flgurc 24A).
In a two compartment model, the tenninal slope from the pos,t-digributive phase of
the curve may bc backextrapolata~ to axnc zero (T). The oegative slope of this line
is teferret-to as beta (O, aot ,B is the tennioal eliminatton tate coostant of the trug.
The iotesept of this lioe on the In plasn coocentration axis is koown as B and is
uset in vanous two~cotnpeneot equations.
Bc~ is similtr to K in to t it vsents the tsminal elim meion r te constant. From it, a
half-life can be cal~ culS
T%, 0.693
is
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Multicompartment Modeling
lEroughout the ame th_t trug is present in the boty, tistribuiion takes place between
the central ant peripheral compartmenu. We can calculate a ratc of tistribuaion
using the mct rcsidxals. This methot estim tes the cffect of distribution on the
ovcrall plasma concentration curvc and uses thc diZfcrcncc between thc cffect of
climination and thc actual plasma consentrations to determinc thc distribution rate.
In the In concentration versus vime curvc in Flgure 24A, the slope of the initial
portion is determined prim--arily by the distribution rate while thc tenninal portion
is determined primarily by thc climination rate.
E <~
100
50
o
S~
PodwDiattibutlon
Ph~
Timo Figsot 24A Plasma druy concentralions with a two-compartment model atter
an imravenous bolus do*c.
Basic Pharmacokinetics
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Multicompartment Modeling
The slope of tbe xsidual line isst, and alpha (a) is the distribution rate constant
for the two-compartment system. The intrcept of the residual line is A. Therefore,
witb the coocept of residuals, we attempt to separate the two pwocsscs of diseribution and climin~ jon.
Ist us now pn~cood through an exampic, applying thc metbot of xsidtis. Draw tbc
plot for thc following cxampb on somilog gnph paper. A dosc of dnag is ad
10.0
50
:!
Z c 10
o
fL Q
Basic Pharmacokinetics
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Multicompartment Modeling
100
5e
Bz
\ Sbpo = a
s -R
Timo
F;
Basic Pharmacokinetics
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Multicompartment Modeling
62
InPtJT 24 63
Tkne afttr
Dose (hr)
0.2S
O.S
1.0
I.S
2.0
4.0
8.0
12.0
16 0
Basic Pharmacokinetics
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Multicompartment Modeling
Plasms
Concentration
(u~/ml)
43
32
20
14
11
6.S
2.8
1.2
0.S2
A linc is trawn connecting the last four points and intcnecting the y-axis. Then, for
the first five points, cxtrapolated values can be cstimated at cach time (0.2S, O.S,
1.0,l.S, and 2.0 hr). If the extrapolated values from the actual plasma concentrations are subtracted, a new set of points is generated (resitual concentration points)
as fts w~
Tlnse dir
Doz (hr)
0.2S
O.S
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Multicompartment Modeling
1.0
1.5
20
^>e
14.S
28.S
13.S
18.S
12.3
7.7
1 1.0
3.0
!O.0
I.D
The zsidual concentrations are then plotted (on semilog paper) versus time, and the
slope of that plot equals 1.8 hr~t. When the negative is dropped, this slope
equals sx; we observe from the plot that the intercept (A) of the line is 4S Fg/ml.
We also can estimate a from the slope of the terminal straight-line portion (equal to
0.21 hr~ ~) and 8 (equal to IS 1lg/ml).
Alpha (ex) must be greater than beta (a), indicating that drug removal from plasma
by distribution into tissues proceeds at a greater rate than does drug removal from
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Multicompartment Modeling
plasma by eliminating organs (e.g., kidncys and liver). rhc initial portion of the
plot is steeper than the terminal portion.
REVIEW PR08LEMS
24.1. Dnw a log pbsma concentntion versus timc profile for a drug Oinimed by the
intravenous bolus nmute and best durizZ by a two-companrnent modeJ (Figure
24D).
242. Tbe slope of the tenninal phase of the above. plot equals
243. Tbe inucept of thc tenniial portion on tbe In pbsma concentstion axis is tenned
>.~ sca(g)~ tbe tenninal const nt of the dmg s it leaves the body.
- the telminal straight-line portioa of the curve. 24.7. The extryolatd points aw
subtmed from tbe actuaJ observed at the correspoading times.
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Multicompartment Modeling
processes ofand
100
50
ca e
Z c 10
FQ
Fkwe 24D
Tim
ljg
Basic Pharmacokinetics
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Multicompartment Modeling
Two-Compartment Model-3
The estimations of A, 8, ss, ant t perforrned in tbe last input are useful for predicing plasrrs concentotions of dmg ch~nzi by a two-compartrnent model. For
Cf ^ Ce e t
where CO is the initial concentration and g is ttne climination rate. Thae two-compartment rnodel (Flgure 2SB) is thc surn of two linear components, reprcsenting
distnbution ant elimination (Flgurc 2SC).
In thc sarnc w y, we can dctrminc dnag consentration (C) at ny tinx (t) by iding thc
two linear components. In cach casc, A or B i-s uset for CO, ant ex or z is used for
XY. Therefe
C, s
+- 8 e~*
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Multicompartment Modeling
C. s Ce e ~
2B
100
501
CO
10
S
Timo Fzwe 25A Pls dmg concentrations with a one com putment model aher an
insvenous bolus dose (first order elimination).
100
50
,o
z -, 10
5
Basic Pharmacokinetics
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Multicompartment Modeling
~c
o
Timc ft 25B Plasma drug concentrations with 3 two compartment model after an
intnvenous boluXs dose sfirst-order elimination) .
100
50
E;
tO
Sz
Tlmo
Fw 25C lOr azmpo~s of a twozxpo~ (>
t) model.
thc equation is
Basic Pharmacokinetics
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Multicompartment Modeling
E or thc twowrat dWibution psramctrs cxist thc centol volurnc {V), thc cxtrapolated volunc (V,~ ,), tbc volunc by arca (V,,, also lcnown as V~|), ant thc stcadystatc vohunc of diwibuX (V,,). Each of thcsc voluncs rclste to diffcrcat undertying
assumptioos.
V dose dox
,~ + B Co
For thc two-compartrnent model, this volurne would bc cquivalent to thc volumc
of the central compartment (V). Thc Ve rclates the amount of drug in thc-central
compartmcnt to the concentration in the central compartment. In thc two-compartrnent model, CO is determined by cxtrapolating back to thc y-axis from the upper
or initial straight-line portioo of the plot.
da
B
V_
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Multicompartment Modeling
wherc B is the w-intetcept of thc line extrapolated from the terminal portion of the
curve. This volume of distribution determination may not provide a useful volume
term since it ovcrsimplifics the two-compartmcnt model and disregards thc distribution phasc.
Another volumc (V,,O or V~) is detcrmined from the area under the plasma concentration vcrsus time curvc and thc tcrminal climination rate constant. This volumc is related as follows:
114
lNvts S 65
vffi
dox
=
CL
ffi x AUC3
va
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Multicompartment Modeling
A ffnal volume tenn is the volume of disttibution at steady state (V,,). Although it
is not affected by changes in drug eliminadoo or ckarance, it is more difficult to
calculate. One way to estimate Vs, is to use the two compartment microconstants:
V,Ve + ~2vf
21
Since-different methods can be used to calculate the various volumes of distribution of a two-compartment model, you should always specify the metbod used.
When reading a pharrnacolcinetic study, pay particular attenion to the method for
calculating thc volume of distribution.
REVIEW PROBLEMS
2S.2. For the two-compurtment model. complete the equo tion describing the
relazionship of plasma concentration with time: C, -
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Multicompartment Modeling
25.3. (True or False) The equation describing elimination afer an intravenous bolus
dose of a drug charauerized by a two-compartment model lequires two exponential
terms.
2!;.4. A patient is given a 500-mg dose of drug by intravenous injection and the
following plasma concentrations result:
Plssms
Time snerConcentrstion
Dese (hr)ItsSml)
Oo ss
0.7S
lS
3
,6
72.0
46.0
33.0
26.3
20.0
Basic Pharmacokinetics
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Multicompartment Modeling
16.6
1r.2
9.0
5.0
_.7
n Rr
Plot the points on semilog paper Ithree cycle) and deterTnine the following: a. ~. b.
B. c. Residual concentrations for the first five points. d. A.
. t.
dose.
S- V,.
PRi4CTlCE SET 2
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Multicompartment Modeling
The following pxbiems are for your xview. Dcfinitions of symbols ant Icey equations = pxvitet hc~:
voluxne of tistribution
C_ tnmugn plsCOOCCD
a steaty state
Basic Pharmacokinetics
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Multicompartment Modeling
k V (I - e~t)
C_Cw e~t
C - t (I ~ e t~)
~ VK (Ie~tD
C_ - Cp e~tt~4
C.4. 4
Vt Ws
Basic Pharmacokinetics
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Multicompartment Modeling
PS2*1. A 60-kg patient is begun on a continuous intravenous infusion of theophylline at 40 mgtbr. a Forty-eight hours after beginning ttte infusion, the plasma concentniion is 12 ~/ml (12 mg/L). If we assume that tbis COncentRtiOD is tbe stcady
state, wb t is the tbeoobylline clearansc?
c. Since we kww V and t. what would the concentntion bc 10 hr aftcr beginning the
infusion?
d. ff the idision i continuet for 3 days ant then discondauet, what woult tD plamS
consentm tion be 12 hr ~r stopping the infwiont
e. If tne infusion is continuct for 3 d ys at 40 mg/ hr ant the stcaty-statc pluma concenttation is 12 Fg/tnl, WDat rate of trug infusion would liltely xsult sn a concentradon of 18 ~/ml?
f. ARcr the iocosed infusion nte above is begun, how bog would it tic to tuch a plu
coo~ cenudon of 18 Fgiml?
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Multicompartment Modeling
b. After thc fifth tese. a peak plasma concentratlon (dsawn at thc ent of thc infusion) is S Ag/ml ant thc ttnugh consentration (drawn right befott thc sixth tosc) is
0.9 Ag/ml. What is thc patients xtual gentamicin half-life? What is thc xtual volume of disvribution?
c. For this patient, what dosc should bc administen:d to reach a new steady-state
peak gentamicin concentration of 8 Fgiml? At this dosc. what will bc thc steadystate trouQh concentration!
II_q
tFoD~ sU
Ce
Basic Pharmacokinetics
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Multicompartment Modeling
(-~lllter)(oln)
o 60
10
5 75
20
5 25
lO
4 80
40
50
50
3 95
90
3 40
150
3 10
180
2 90
240
2 55
28S
o. Caleelete the ter lnal half-llfe (t~) the hybrid rete eonetento
nd O nd the coefflelente (~1 3 Sl) for gent- leln to theeo he-odlulyal~ putlente
b. tor ubJecte vith noreel renal functlon. the yete-le elearence (Cl~) of gentanletn
le pproalaetel1 0.041 llter/ In. Sec uee 98X ef Cl~ le due to excretlon of
unchanged drug. renel tciluro utll ~rkedly effect ~ent~lcin clecr~nce.
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Multicompartment Modeling
nd the ell fnetlon rete eonetont. Uhet frectton of tho gt ted eln ln the body fter 3
hr nlght be la the peripherel ee part~ent7 At vh t tbae doee the gent _ Icin in the
peripherel ee pert~ent rench
~t
. Wlthout the hc odielyrer two ~ale petlente ach xhlbited creetinine eleorence
(Cle ) of 5 llwin; the norx~l velue le 117 t 20 I/nin. A~using that the deereFeed
Clcr {e due to decresce In glo-eruler filtretloo rcte vhst vould h-ve beeD the renel
clecrxnce (Clr) of gent~elcia In there two patlentn hed they rz cined vithout the heodlolysert Uhct done vould then need to be dsinletered every hr to n Intoin (C~ t
4 tert Co pcro your eouer wStb tho thy~telea e Deek Refer neo.
Vancomycin is an antibiotic used in the treatment of endocarditis in patients allergic to penicillin. It is poorly absorbed orally and acute pain is associated with intermuscular injection. I.V. is the route of choice. After a 1 gm I.V. dose the following
data is observed:
Basic Pharmacokinetics
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Multicompartment Modeling
.5
51
1.0
36
1.5
28
2.0
23
3.0
18.5
4o
16
6.0
12.5
8.0
99
12.0
6.25
FIND: a) A1 ;
b) alpha
c) Clearance ;
Clearance:
Basic Pharmacokinetics
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Multicompartment Modeling
The following data was collected from a normal patient in the revious study (Welling, op. cit.) following an IV bolus injection of 500 mg of erythromycin (as lactobionate salt ).
12 4
3 2.6
6.4
4 1.9
4.0
6 1.2
8 0.4
~.
Fmd the peak time in the peripheral compartment.the fraction of the drug in the
peripheral compartment at four hours.
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Multicompartment Modeling
Time (minutes)Concentration
10
63
20
51
30
43
45
35
60
30
120
183
240
7.6
360
3.2
FIND:
(5 points) a) A^V1^V =
(5 points) b) B^V1^V =
(5 points) c) Clearance =
Basic Pharmacokinetics
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Multicompartment Modeling
63
20
51
30
43
45
35
60
30
120
18.3
240
7.6
360
3.2
Basic Pharmacokinetics
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Multicompartment Modeling
Time mcg/ml
1
1.67
1.22
.97
.83
.66
.56
12
.42
18
.27
24
.17
30
.11
Find A1, B1, alpha, beta, K10, K12, K21, Peak time in the peripheral
compartment, % in the peripheral compartment at equilibrium.
Can you assume that this drug can be estimated by a one compartment
model upon multiple dosing ?
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Multicompartment Modeling
PARAMETER
C1 renal (ml/min/kg)
2.61 (1.10)
0.71 (0.16)
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Multicompartment Modeling
6.69 (4.03)
6.44 (1.63)
8.53 (0.81)
1.85
(0.19)
% bound to protein80.00(2.50)
During the last pharmacokinetic exam you noticed ome cardiac problems.
Wh n you ch-cked with your physician, He prescribes quinidine. What
dose should you be on?
Later, he diagnoses mononucliosis from lack of sleep and poor ating h bits s weli
as cardiac arrythmias. Your liver funcion has dropped to 60* of normal. He prescribes quinidine for you. What is the dose that you should be on ?
ie. -
ll-3
Basic Pharmacokinetics
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260, 300 and 325 mg tablets, while quinidine gluconate is available in 325 mg tablets. The following pharmacokinetic parameters are reported by Ueda:
During the last pharmacokinetic exam you noticed some cardiac problems. When
you checked with your physician, He prescribes quinidine. What dose should you
be on?
Later, he diagnoses mononucliosis from lack of sleep and poor eating habits as
well as cardiac arrythmias. Your liver funcion has dropped to 60% of normal. He
prescribes quinidine for you. What is the dose that you should be on ?
Basic Pharmacokinetics
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Multicompartment Modeling
Methotrexate is a cytolytic used for the treatment of acute leukemia and other
forms of cancer. After a a 400 mg/kg dose the following data was recorded for a 12
y/o boy.
Time (hours)
6
12
18
36
48
60
72
90
2
1.2
0.46
0.36
0.15
Basic Pharmacokinetics
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Multicompartment Modeling
PROBLEM SET
zumper w~wFS
t
L) v
, ~ s D fv
Patients suffering chronic renal failure often require hemodialysis. Drugs may be
administered by injection into the venous side of the hemodialyzer machine.
Such a situation was described by L*tourneau-Saheb et al (Int. J. Clin. PKinmacol., 15, 116-120 (1977)) for six patients who receivet an intravenous dose 7 gentamicin (90 mg). The mean serum concentrations of gentamicin (Cs) showed a
biexponential decline with time (t).
(~9cyml)
(mRn)
6.60
10
5-75
20
5.25
30
4.80
40
4.50
50
3.95
90
3.40
150
Basic Pharmacokinetics
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Multicompartment Modeling
3.10
180
2.90
240
2.55
285
.
(a) Calculate the values of t1/29 B, Bj, ~, A~, and V1. LFtourneau
Saheb et al reported,
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Multicompartment Modeling
_1
11-33
(c) Under the conditions of hemodialysis, calculate the dose (D) of gentamicin
which would be administered every 8 hr (t) in order to maintain an Waverage
steady-state serum concentration of 4 ug/ml. What would be (Cmax)ss and
(Cmin)ss?
(d) Without the hemodialyzer two male patients each exhibited a creatinine clearance (Clcr) of S ml/min; the noW l value is 117 + 20 ml/min. Assuming that the
decreased ClCr is due to a decrease in glomerular filtration rate, what would have
been the renal clearance (Clr) of gentamicin in these two patients had they
remalned without the hemodialyzer? What dose would then need to be administered every 8 hr to maintajn (~s) at 4 ug/ml? Compare your answer with the Physicians Desk Reference (5677).
Your third patient comes from Edelman et al (Clin Pbarmacol Therap 35:382-6
(1984)). He studied metotrexate is artbritic patients. The pharmacokinetic parameters gleened from the 10 mg IV data arc:
A1 (mg/L) 0.663 Alpha (hr-1) 059 B1 (mg/L) 0.073 Beta (hr-1) 0.097
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Multicompartment Modeling
19) What is the t(max) in the perepheral compartment (hr) ? a) 0 b) 1.8 c) 3.7 d) 5.1
e)6.1
Two compartment: It has been proposed (Ionescu et al. Clin Pkin 14:178186,1988) that morphine injectcd dirtctly into thc spioal chord would give significant analgesia. The following is a CSF concentration - time profile resulting from
05 mg/lcg IV bolus dose of Morphine:
Basic Pharmacokinetics
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Multicompartment Modeling
time
conc.
(min) (mg/L)
time
conc.
(min) (mg/L)
251
120
323
181
240
173
10
142.5
360
82
20
1043
480
2.4
40
75.1
720
1.2
80
48.8
1 a) fraction of remaining drug contained in peripheral compartment at equilibrium. Lb) Can this drug be approximated by a one compartment model ? Support
your contention with calculations. Lc) Calculate a rcasonable dosage regimen for
the above patient to maintain the concentration within the therapeuticwindow of
50 to 5 mg/L.
Two compartment:
(1) It has been proposed that diazepam has anticonvulsant properties above 350
nanograms per milliliter. The following is a concentration - time profile resulting
from 10 mg IV bolus dose of diazepam :
time
conc. time
(hrs)
(ng/ml)(hrs)
0.25
480
6.0
Basic Pharmacokinetics
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Multicompartment Modeling
0-50
400
8.0
l.o
300
10.0
2.0
170
16.0
3.0
120
24.0
on
llo
~_
conc.
(ng/ml)
100
90
85
70
53
Dlezzewm
Basic Pharmacokinetics
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Multicompartment Modeling
UA tD 20A
AD
Time
Basic Pharmacokinetics
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Multicompartment Modeling
= 0.78
l.b) Can this drug be approximated by a one compartment model? Support your
contention with calculations.
Since the beta phase contributes more than 80% of the total AUC, the model can
be collapsed to a one compartment model.
l.c) Calculate a reasonable dosage regimen for the above patient to maintain the
concentration within the therapeutic window of 350 to 1100 nanograms per ml.
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Tau max = 27.39 * 1.65 = 45.19 hr drop the dosing interval to 24 hours now need
to find a new N
N = 24 / 27.39 = 0.876
To find dose:
l.lOOmg/L = (D / 97.25 L) * tl / (1 - 0.5^0.876^)]
D = 49 mg daily (aggressive therapy)
Two Compartment:
sos
Basic Pharmacokinetics
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Multicompartment Modeling
theophylilne
.
i ,_
1.
OD
2D
4wD 6D8S
tD
Tlm~
Time (hr.)
0.167
0.333
0.500
0.833
1.0
1.5
2.0
3.0
4.0
6.0
Basic Pharmacokinetics
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8.0
Conc. (mg./L.)
20.3
are as follows:
18.1
A1 (mg/L)16.1
16.1
B1 (mg/L)17.9
15.6
Alpha (hr-l)4.8
14.3
Beta (hr-l)0.15
13.3
11.
9.8
7.3
s.4
Basic Pharmacokinetics
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11-78
Multicompartment Modeling
(L/Kg) ?
A) 0.165 *B) 0.30C) 0.35D) 2.9E) 6.1
A) 12 B) 23
Basic Pharmacokinetics
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11-79
Multicompartment Modeling
B1 are about the same value. is bigger than beta contribution of the alpha phase
AUC is the total AUC. contribution of the beta the total AUC.
phase AUC is
6) What is the mean residence time (MRT) for the IV dose (hr) ?
AUC (O to inf)
AUMC (O to inf)
Basic Pharmacokinetics
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Multicompartment Modeling
A) 8.0 B) 8.75
122
1400
8) What is the mean absorption time (MAT) for the oral dose (hr)?
A) 1
B) 2
C) 3
D) 4
*E) 5
(hr^T-l^T) ?
Basic Pharmacokinetics
REV. 99.4.25
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Multicompartment Modeling
Basic Pharmacokinetics
REV. 99.4.25
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11-82
Multicompartment Modeling
9) What is your patients effective rate of elimination (hr^-l)? a) 0.112 *b) 0.162 c)
0.5 d) 4.29 e) 6.19
RP s angina was controlled on 40 mg TID of propranolol. You calculated his pharmacokinetic parameters to be: Vd (L) = 125; T1/2 (hr) = 3.1; Qh (L/hr) = 33; Bioavailability (f) = .7; Bound(%) = 95. Propranolol is essen^_ tially 100%
metabolized.
12) What is his Total body clearance (L/hr)? a) 1.4 b) 14 *c) 28 d) 33 e)40.3
Basic Pharmacokinetics
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11-83
Multicompartment Modeling
e) 1.22
He is now suffering from renal failure. His half life went up to 3.8 hr while his
binding went up to 98.3% because of an increase in AAG, a plasma protein to
which propranolol binds.
Basic Pharmacokinetics
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11-84
Multicompartment Modeling
19) What will his new Cpss max free be if we keep him on the same
regimen (ng/mL)?
20) What is his new Cpss max total(ng/ml) ? a) 5.26 b) 7.5 *c) 310 d) 442 e) 554
Basic Pharmacokinetics
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Multicompartment Modeling
22) The physician sees that the clearance has dropped and consequently the total
plasma concentrations have gone up. He wants to decrease to dose to 40 mg / BID.
What would you recommend? a) Sounds good to me. That will get the Cpss max
total concentration back to it was before he was sick. b) His new clearance was
marginally changed because the drug is cleared by the liver. Id leave it alone. c) I
think the change from TID to BID is a bit much. How about lowering it to 30 mg
instead of 40 mg TID. *d) We need to increase the dose, not lower it. Id recommend 40 mg QID. e) We need to increase the dose, not lower it. Id recommend 80
mg QID.
Two compartment
Methotrexate is a cytolytic used for the treatment of acute leukemia and other
forms of cancer. After a a 400 mg/kg dose the following data was recorded for a 12
y/o boy.
360
12
70
18
15
36
48
1.2
60
0.46
72
036
Q(}
0.15
Basic Pharmacokinetics
REV. 99.4.25
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11-86
Multicompartment Modeling
Everything.
Primiflnne. Phenabarbital
0.9
09
Vd (L/Kg)
0.7
T1/2
0.6
7 hr
5 days
% Excreted undhanged2520
% Metabolized75
80
Basic Pharmacokinetics
REV. 99.4.25
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11-87
Multicompartment Modeling
% Metabolized to Phenobarbital25*~
2.(20 pts) Please prepare a short consult for your M.D. in which you caSculate a
dosage regimen for an 80 kg
patient whidh would l~eep the plasma concentration within the therapeutic range.
Prirnidone comes as 250 mg
scored (can be broken in half) tablets. Indude your average, maximum and minimum primidone as well as
phenobarbital steady-state concentrations in the consult.
3. (25 pts) The patient recently contracted mono. His liver function has been
reduced to 50 % of normal.
Would you recommend a change in your therapy ? If you would, prepare a short
consult for his M.D. as in question #2. Dont forget that changes in hepatic clearance result in changes in both phenobarbital clearance 5~nfl fannation
4. (25 pts) Now that his mono has cleared up the doctor noticed that he has stenosis
of the liver as a consequence of all t_e heavy parting that he did after the kinetics
course. His liver plasma flow has been reduced to 50 % of normal. Would you recommend a dhange in therapy ? If you would, prepare a short consult for his M.D.
as in question #2. Dont forget that dhanges in hepatic dearance result in changes
in both phenobarbital dearance and formation.
Basic Pharmacokinetics
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Multicompartment Modeling
Basic Pharmacokinetics
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Multicompartment Modeling
11.4 Begin
Basic Pharmacokinetics
REV. 99.4.25
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11-90
Multicompartment Modeling
11.5 Problems
Basic Pharmacokinetics
REV. 99.4.25
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11-91
Multicompartment Modeling
Aspirin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 1)
AHFS 00:00.00
GPI: 0000000000
Fu, C., Melethil, S., and Mason, W., "The pharmacokinetics of aspirin in rats and the effect of buffer", Journal of Pharmacokinetics
and Biopharmaceutics, Vol. 19, (1991), p. 157 - 173.
Aspirin is an analgesic/ antipyretic commonly used to relieve minor pain and is used in such conditions as rheumatic
fever, rheumatoid arthritis, and osteoarthritis. The major metabolite of aspirin is salicylic acid. The following set of
data was collected using rats which weighed 250 - 300 g.
PROBLEM TABLE 11 - 1.
Aspirin
weight of rat
275 g
Dose
5 mg/kg IV
A1
8.58
1.07
B1
7.24
0.2
AUC
38.8
AUMC
116.0
1.
What is ?
2.
What is ?
3.
4.
5.
6.
7.
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
What is ?
14.
15.
16.
17.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-92
Multicompartment Modeling
Buprenorphine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 2)
AHFS 00:00.00
GPI: 0000000000
Ohtani, M., et al., "Pharmacokinetic analysis of enterohepatic circulation of buprenorphine and its active metabolite, norbuprenorphine, in rats", Drug Metabolism and Disposition, Vol. 22, (1994), p. 2 - 7.
Buprenorphine is a morphine derivative which has twice the duration of action and 30 times the potency of morphine.
Buprenorphine is partially metabolized to norbuprenorphine which is also active in the body. In this study, buprenorphine was given to rats weighing 280 - 300 g.
PROBLEM TABLE 11 - 2.
Buprenorphine
Weight of rat
290 g
Dose
0.06 mg/kg IV
A1
41
3.89
B1
10
0.271
AUC
48.3
AUMC
135.24
1.
What is the ?
2.
What is the ?
3.
4.
5.
6.
7.
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
What is ?
14.
15.
16.
Basic Pharmacokinetics
REV. 99.4.25
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11-93
Multicompartment Modeling
17.
Basic Pharmacokinetics
REV. 99.4.25
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11-94
Multicompartment Modeling
Caffeine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 3)
AHFS 00:00.00
GPI: 0000000000
Shi, J., et al., "Pharmacokinetic-pharmacodynamic modeling of caffeine: Tolerance to pressor effects", Clinical Pharmacology
and Therapeutics, Vol. 53, (1993), p. 6 - 14.
This study looks at the cardiovascular effects of caffeine. Caffeine is known to increase blood pressure upon its withdrawl. This study looks at how tolerance to caffeine and its pressor effects develops and disappears with time.
PROBLEM TABLE 11 - 3.
Caffeine
Patient weight
80 kg
Dose
4 mg/kg oral
A1
10.55
4.9
B1
9.1
0.23
98.4 %
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
13.
What is ?
14.
15.
16.
Basic Pharmacokinetics
REV. 99.4.25
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11-95
Multicompartment Modeling
Cefazolin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 4)
AHFS 00:00.00
GPI: 0000000000
Nightingale, C., et al., "Changes in pharmacokinetics of cefazolin due to stress", Journal of Pharmaceutical Sciences, Vol. 64,
(1975), p. 712 - 714.
Cefazolin is a cephalosporin antibiotic used in the treatment of many types of infections. This study looks at the effect
of stress on the pharmacokinetics of cefazolin. The following data was approximated from the graph given in this article.
PROBLEM TABLE 11 - 4.
Cefazolin
Patient weight
56.3 kg
Dose
1 g IV
A1
206.48
4.832
B1
122.96
0.573
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-96
Multicompartment Modeling
Ceftazidime
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 5)
AHFS 00:00.00
GPI: 0000000000
Ackerman, B., et al., "Effect of decreased renal function on the pharmacokinetics of ceftazidime", Antimicrobial Agents and Chemotherapy, Vol. 25, (1984), p. 785 - 786.
Ceftazidime is a cephalosporin antibiotic. This study explores the effect of compromised renal function on the pharmacokinetics of ceftazidime. The following data was approximated from the graph given in this article.
PROBLEM TABLE 11 - 5.
Ceftazidime
Dose
1 g IV bolus
A1
188
8.22
B1
58.2
0.49
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-97
Multicompartment Modeling
Clentiazem
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 6)
AHFS 00:00.00
GPI: 0000000000
Shah, A., et al., "Pharmacokinetics of clentiazem after intravenous and oral administration in healthy subjects", Journal of Clinical Pharmacology, Vol. 33, (1993), p. 354 - 359.
Clentiazem is an derivative of diltiazem which is under investigation for its use in the treatment of angina pectoris and
hypertension. Clentiazem blocks calcium channels resulting in a decrease in peripheral vascular resistance which subsequently leads to a decrease in blood pressure.
PROBLEM TABLE 11 - 6.
Clentiazem
Patient weight
77 kg
Dose
20 mg IV bolus
A1
37.52
2.7
B1
16.17
0.078
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
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11-98
Multicompartment Modeling
Cocaine
(Problem 11 - 7)
AHFS 00:00.00
GPI: 0000000000
Levine, B. and Tebbett, I., "Cocaine pharmacokinetics in ethanol-pretreated rats", Drug Metabolism and Disposition, Vol. 22,
(1994), p. 498 - 500.
This study looks into several reports which claim that the euphoric effects of cocaine can be enhanced when taken in
conjunction with alcohol. This effect may be the result of higher cocaine blood levels or a reduced elimination of
cocaine or a combination of both.
PROBLEM TABLE 11 - 7.
Cocaine
Weight of rat
300 g
Dose
A1
1172.6
0.362
B1
462
0.045
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
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11-99
Multicompartment Modeling
1,2-Diethyl-3-Hydroxypyridine-4-One
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 8)
AHFS 00:00.00
GPI: 0000000000
Epemolu, O., et al., "The pharmacokinetics of 1,2-Diethyl-3-Hydroxypyridine-4-One (CP94) in rats, Drug Metabolism and Disposition, Vol. 20, (1992), p. 736 - 741.
1,2-Diethyl-3-Hydroxypyridine-4-One (CP94) is an iron chelator which is orally active. It is being investigated for use
in the treatment of hemoglobinopathic disorders. In this study, rats weighing 250 - 300 g were given doses 50 mg /kg
intravenously and the following data was collected:
PROBLEM TABLE 11 - 8.
1,2-Diethyl-3-Hydroxypyridine-4-One
Weight of rat
275 g
Dose
50 mg/kg IV
A1
30.9
2.03
B1
8.13
0.38
Assume that the rat ( which weighs 275 g) is suffering from thalassemia and his iron levels are very high. The rat is
prescribed CP94 to restore the iron levels to normal.
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
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11-100
Multicompartment Modeling
2,2-dimethylaziridine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 9)
AHFS 00:00.00
GPI: 0000000000
Lalka, D., Jusko, W., and Bardos, T., "Reactions of 2,2-dimethylaziridine-type alkylating agents in biological systems II: Comparative pharmacokinetics in dogs", Journal of Pharmaceutical Sciences, Vol. 64, (1975), p. 230 - 235.
The 2,2-dimethylaziridine alkylating agents are used for their antitumor capability as antineoplastic agents. In this
study, male mongrel dogs, weighing 20 - 28 kg, were each given a dose of 12 mg/kg of ethyl bis (2,2-dimethylaziridinyl) phosphinate intraveneously.
PROBLEM TABLE 11 - 9.
2,2-dimethylaziridine
Weight of dog
24 kg
Dose
12 mg/kg IV
A1
42
0.409
B1
8.5
0.095
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
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11-101
Multicompartment Modeling
Flurbiprofen
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 10)
AHFS 00:00.00
GPI: 0000000000
Menzel-Soglowek, S., et al., "Variability of inversion of (R)-flurbiprofen in different species", Journal of Pharmaceutical Sciences,
Vol. 81, (1992), p. 888 - 891.
Flurbiprofen is an anti-inflammatory and analgesic agent. This study compares the pharmacokinetics of the (R)-isomer
of flurbiprofen to the those of the (S)-isomer. The following data was approximated from the graph given in this article.
PROBLEM TABLE 11 - 10. Flurbiprofen
Weight of rat
260 g
Dose
10 mg/kg IV
A1
48.5
2.33
B1
57.68
0.175
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
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11-102
Multicompartment Modeling
Furosemide
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 11)
AHFS 00:00.00
GPI: 0000000000
Tilsone, W., and Fine, A., "Furosemide kinetics in renal failure", Clinical Pharmacology and Therapeutics, Vol. 23, (1978), p. 644
- 650.
Furosemide is an agent which is used for its diuretic action to treat such conditions as renal and cardiac edema. In this
study, normal subjects were given an intravenous bolus dose of 22 mg of furosemide. Blood samples were taken at various intervals and the following data was obtained:
PROBLEM TABLE 11 - 11. Furosemide
Dose
22 mg IV
A1
2.1
6.9
B1
0.77 -
0.96
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-103
Multicompartment Modeling
Glycyrrhizin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 12)
AHFS 00:00.00
GPI: 0000000000
Tsai, T., et al., "Pharmacokinetics of glycyrrhyzin after intravenous administration to rats", Journal of Pharmaceutical Sceinces,
Vol. 81, (1992), p. 961- 963.
Glycyrrhizin is a component of licorice which is proposed to have anti-inflammatory, anti-hepatotoxic, interferoninducing, anti-viral, and anti-ulcer activity. It also causes pseudoaldosteronism. The following data was approximated
from the graph given in this article.
PROBLEM TABLE 11 - 12. Glycyrrhizin
Weight of rat
275 g
Dose
20 mg/kg
A1
91.23
4.16
B1
69.90 -
0.43
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-104
Multicompartment Modeling
Human Deoxyribonuclease
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 13)
AHFS 00:00.00
GPI: 0000000000
Mohler, M., et al., "Altered pharmacokinetics of recominant human deoxyribonuclease in rats due to the presence of a binding protein", Drug Metabolism and Disposition, Vol. 21, (1993), p. 71 - 75.
Deoxyribonucleases are found in human serum, urine, and a variety of tissues. These endonucleases catalyze the
hydrolysis of DNA to oligonucleotides. It has been suggested that increased levels of serum deoxyribonucleases may
predict malignancies.
PROBLEM TABLE 11 - 13. Human
Deoxyribonuclease
Patient weight
260 g
Dose
1 mg/kg IV bolus
A1
19250 -
8.61
B1
4897
0.229
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
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11-105
Multicompartment Modeling
(Problem 11 - 14)
AHFS 00:00.00
GPI: 0000000000
Tanaka, H., and Kaneko, T., "Pharmacokinetic and pharmacodynamic comparisons between human granulocyte colony-stimulating factor purified from human bladder carcinoma cell line 5637 culture medium and recombinant human granulocyte colonystimulating factor produced in Escherichia coli", The Journal of Pharmacology and Experimental Therapeutics, Vol. 262, (1992),
p. 439 - 444.
Human Granulocye Colony-Stimulating Factor (hG-CSF) is used to stimulate the proliferation of precursor cells and
their subsequent differentiation in the bone marrow. This article compares the pharmacokinetics of hG-CSF produced
by two different methods. In the first method, the hG-CSF was obtained from human bladder carcinoma cell line 5637
culture medium. In the second method, the hG-CSF was produced by Escherichia coli.
PROBLEM TABLE 11 - 14. Human
Weight of rat
250 g
Dose
10 g/kg IV
A1
B1
99.228
1.27 hours
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is a?
8.
What is b?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-106
Multicompartment Modeling
Hydrocortisone
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 15)
AHFS 00:00.00
GPI: 0000000000
Derendorf, H., et al., "Pharmacokinetics and oral bioavailability of hydrocortisone", Journal of Clinical Pharmacology, Vol. 31,
(1991), p. 473 - 476.
This study looks at both the two-compartment model pharmacokinetics and the oral bioavailability of hydrocortisone.
The following data was approximated from the graph given in this article.
PROBLEM TABLE 11 - 15. Hydrocortisone
Dose
20 mg IV
A1
430
13.1
B1
439 -
0.445
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-107
Multicompartment Modeling
Levodopa
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 16)
AHFS 00:00.00
GPI: 0000000000
Sasahara, K., et al., "Dosage form design for improvement of bioavailability of levodopa II: Bioavailability of marketed levodopa
preparations in dogs and parkinsonian patients" Journal of Pharmaceutical Sciences, Vol. 69, (1980), p. 261 - 265.
Levodopa is an agent used in the treatment of Parkinson's disease. This study looks at various dosage forms of
levodopa and compares the pharmacokinetic parameters of each. The following data was approximated from the graph
given in this article.
PROBLEM TABLE 11 - 16. Levodopa
Dose
50 mg IV
A1
8.63
13.3
B1
2.97 -
1.14
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-108
Multicompartment Modeling
Meropenem
(Problem 11 - 17)
AHFS 00:00.00
GPI: 0000000000
Chimata, M., et al., "Pharmacokinetics of meropenem in patients with various degrees of renal function, including patients with
end-stage renal disease", Antimicrobial Agents and Chemotherapy, Vol. 37, (1993), p. 229 - 233.
Meropenem is a carapenem antibiotic which has a broad spectrum of activity. It is used in the treatment of infections
caused by both Gram-positive and Gam-negative bacteria and is active against Enterobacteriaceae and Pseudomonas
aeruginosa. Meropenem is 60% renally and 40% hepatically eliminated.
PROBLEM TABLE 11 - 17. Meropenem
Dose
A1
21
1.85
B1
20 -
0.503
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-109
Multicompartment Modeling
N-Methylpyridinium-2-Carbaldoxime Chloride
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 18)
AHFS 00:00.00
GPI: 0000000000
Bodor, N., and Brewster, M., "Problems of delivery of drus to the brain", International Encyclopedia of Pharmacology and Therapeutics, Vol. 120, (1975)
N-methylpyridinium-2-cabaldoxime chloride (2-PAM) is the drug of choice for the treatment of orgaonphosphate poisoning. It is mostly renally excreted. This article considers the fact that this agent is highly hydrophilic and thus has
difficulty reaching the brain. The following data was approximated from the graph given in this article.
PROBLEM TABLE 11 - 18. N-Methylpyridinium-2-Carbaldoxime
Weight of dog
40 kg
Dose
7.0 mg/kg
A1
5.356
0.28796
B1
35.983
11.586
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
Chloride
11-110
Multicompartment Modeling
Pyrazine Diazohydroxide
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 19)
AHFS 00:00.00
GPI: 0000000000
Vogelzang, N., et al., "Phase I and pharmacokinetic study of a new antineoplastic agent: pyrazine diazohydroxide (NSC 361456)",
Journal of Cancer Research , Vol. 54, (1994), p. 114 - 119.
Pyrazine diabhohydroxide is an agent which forms a reactive pyrazine dizonium ion in vivo which acts to destroy
tumor cells. This study looks at the pharmacokinetic parameters of this agent in advanced cancer patients whose cancer
was not curable by any other type of therapy. They were given a dose of 18 mg/m2/day for 5 days every 4 weeks.
Most of the following data was collected for a 66 year old male subject. The remaining data was approximated from
the graph given in this article.
PROBLEM TABLE 11 - 19. Pyrazine
Diazohydroxide
1.82 m2
Dose
18 mg/ m2
A1
8063
0.195
B1
1186
0.0257
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-111
Multicompartment Modeling
Terbinafene
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 20)
AHFS 00:00.00
GPI: 0000000000
Kovarik, J., et al., "Dose-proportional pharmacokinetics of terbinafine and its N-demethylated metabolite in healthy volunteers",
British Hournal of Dermatology, Vol. 126, (1992), p. 8 - 13.
Terbinafene is an antifungal agent which acts by interfering with ergosterol biosynthesis. It is active against Trichophyton, Epidermophyton, and Microsporum. Approximately 70% of an oral dose is absorbed. Terbinafene has an Ndemethylated metabolite which is active. The following data was approximated from the graph given in this article.
PROBLEM TABLE 11 - 20. Terbinafene
Dose
750 mg
A1
2398
0.511 -
B1
102 -
0.0222 -
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-112
Multicompartment Modeling
Verrucarol
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 21)
AHFS 00:00.00
GPI: 0000000000
Barel, S., Yagen, B., and Bailer, M., "Pharmacokinetics of the trichothecen mycotoxin verrucarol in dogs", Journal of Pharmacetuical Seciences, Vol. 79, (1990), p. 548 - 550.
Verrucarol is a toxin which is related to toxins which have anti-tumor activity. This study looks at the pharmacokinetics of verrucarol in dogs. The following data was approximated from the graph given in this article.
PROBLEM TABLE 11 - 21. Verrucarol
Weight of Dog
22.5 kg
Dose
0.4 mg/ kg
A1
126.05
0.0415
B1
540.58 -
0.00946-
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
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11-113
Multicompartment Modeling
2-Chloro-2-deoxyadenosine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 22)
AHFS 00:00.00
GPI: 0000000000
Liliemark, J. and Juliusson, G., "On the pharmacokinetics of 2-Chloro-2-deoxy-adenosine in humans", Cancer Research, Vol. 51,
(1991), p. 5570 - 5572.
Two-Chloro-2-deoxyadenosine is an antitumor agent used in the treatment of hairy cell leukemia and other lymphoproliferative diseases. Infusions of 0.14 mg/kg over 12 hours were administered to 12 patients with various lymphoproliferative diseases for 5 consecutive days. The following data was collected:
PROBLEM TABLE 11 - 22. 2-Chloro-2-deoxyadenosine
Patient weight
65 kg
Dose
A1
177.0 nM
1.04
B1
21.0 nM
0.10
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-114
Multicompartment Modeling
Felodipine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 23)
AHFS 00:00.00
GPI: 0000000000
Regardh, C., et al., "Pharmacokinetics of felodipine in patients with liver disease", Journal of Clinical Pharmacology, Vol. 36,
(1989), p. 473 - 479.
The pharmacokinetic parameters of felodipine in patients with impaired liver function were investigated in this study.
Felodipine blocks calcium channels resulting in a decrease in peripheral vascular resistance which subsequently leads
to a decrease in blood pressure. Felodipine also works as a diuretic. The bioavailability of felodipine is 15%. It is
highly (99.64%) protein bound and is eliminated almost exclusively by liver metabolism. The following data is for a
patient with liver cirrhosis:
Weight of dog
kg
Dose
mg/kg IV
A1
a
B1
b
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-115
Multicompartment Modeling
Lorazepam
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 24)
AHFS 00:00.00
GPI: 0000000000
Segal, J., et al., "Decreased systemic clearance of lorazepam in humans with spinal cord injury", Journal of Clinical Pharmacology, Vol. 31, (1991), p. 651 - 656.
Lorazepam is a benzodiazepine which is used as an anxiolytic, an anti-convulsant, an anti-emetic, and a sedative-hypnotic agent.
PROBLEM TABLE 11 - 24. Lorazepam
Dose
A1
a
B1
b
AUC
AUMC
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-116
Multicompartment Modeling
Metronidazole
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 25)
AHFS 00:00.00
GPI: 0000000000
Uccellini, D., Morgan, D., and Raymond, K., "Relationships among duration of infusion, dose, dosing interval, and stedy-state
plasma concentrations during intermittent intravenous infusions: studies with metronazole", Journal of Pharmacokinetics and
Biopharmaceutics, Vol. 14, (1986), p. 95 - 106
Patient weight
70 kg
Dose
1.5 g IV infusion
A1
a
2.11
B1
b
0.09
AUC
AUMC
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-117
Multicompartment Modeling
Rhizoxin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 26)
AHFS 00:00.00
GPI: 0000000000
Graham, M., et al., "Preclinical and phase I studie with rhizoxin to apply a pharmacokinetically guided dose-escalation scheme",
Journal of the National Cancer Institute, (1991), p. 494 - 499.
Rhizoxin is a lactone which was obtained from the fungus, Rhizopus chinensis. It has anti-tumor activity
against a broad spectrum of tumor types including LOX melanoma, A549 lung tumors, and MX-1 mammary
tumors. This study looks at dosing of rhizoxin. Patients with nontreatable tumors who had a life expectancy
of more than 12 weeks were given doses of 12 mg/ m2. The following data was approximated from the
graph given in this article.
PROBLEM TABLE 11 - 26. Rhizoxin
1.82 m2
Dose
12 mg/ m2
A1
1.55
4.00
B1
0.12
0.116 -
1.
What is ?
2.
What is ?
3.
What is ?
4.
5.
6.
7.
What is ?
8.
What is ?
9.
What is ?
10.
What is ?
11.
What is ?
12.
What is ?
13.
14.
15.
Basic Pharmacokinetics
REV. 99.4.25
http://kiwi.creighton.edu/pkinbook/
11-118
Multicompartment Modeling
11.5.1
The following set of equations were used to solve the two-compartment model problem set. The problem sets for the
first three drugs have been done for you. The others are done the same way. The answers for all of the problems are in
the back of this packet.
Aspirin
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Yes
_____________________________________________________________________
Buprenorphine
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Basic Pharmacokinetics
REV. 99.4.25
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11-119
Multicompartment Modeling
12.
13.
14.
15.
Yes
_____________________________________________________________________
Caffeine
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
11.5.2
Yes
ANSWERS
Aspirin
1.
8.019
2.
36.2
3.
31.1
4.
2.62 minutes
5.
155.48 mL
6.
86.92 mL
7.
81.57 mL
Basic Pharmacokinetics
REV. 99.4.25
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11-120
Multicompartment Modeling
8.
0.648 min
9.
3.47 min
10.
0.598 min-1
11.
0.358min-1
12.
0.314min-1
13.
15.82
14.
1.928 minutes
15.
44.1%
16.
Yes
17.
0.381 min-1
Buprenorphine
1.
10.54
2.
36.9
3.
47.4
4.
366.8
5.
2.85 hours
6.
1.35 L
7.
0.34 L
8.
0.178 hours
9.
2.58 hours
10.
0.981 h-1
11.
1.075 h-1
12.
2.11 h-1
13.
51
14.
0.736 hours
15.
74.9%
16.
No
17.
Can't be calculated
Caffeine
1.
2.15
2.
39.57
3.
41.72
Basic Pharmacokinetics
REV. 99.4.25
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11-121
Multicompartment Modeling
4.
7.67
5.
33.35 L
6.
16.28 L
7.
0.141 hours
8.
3.014 hours
9.
2.39 h-1
10.
0.471 h-1
11.
2.266 h-1
12.
19.65
13.
0.655 hours
14.
51.2%
15.
Yes
Cefazolin
1.
42.73
2.
214.59
3.
257.32
4.
3.89
5.
6.78 L
6.
3.035 L
7.
0.143 hours
8.
1.21 hours
9.
2.163 h-1
10.
1.28 h-1
11.
1.96 h-1
12.
329.44
13.
0.50 hours
14.
55.2%
15.
Yes
Ceftazidime
1.
22.87
2.
118.78
Basic Pharmacokinetics
REV. 99.4.25
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11-122
Multicompartment Modeling
3.
141.65
4.
7.0598
5.
14.41 L
6.
4.06 L
7.
0.0843 hours
8.
1.415 hours
9.
2.32 h-1
10.
1.738 h-1
11.
4.65 h-1
12.
246.2
13.
0.365 hours
14.
39.2%
15.
Yes
Clentiazem
1.
13.9
2.
207.3
3.
221.2
4.
90.4
5.
1159.2 L
6.
372.5 L
7.
0.257 hours
8.
8.89 hours
9.
0.868 h-1
10.
0.243 h-1
11.
1.67 h-1
12.
53.69
13.
1.35 hours
14.
47.4%
15.
Yes
Cocaine
1.
3239.2
2.
10266.7
Basic Pharmacokinetics
REV. 99.4.25
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11-123
Multicompartment Modeling
3.
13505.89
4.
44.43
5.
987.2 mL
6.
367.1 mL
7.
1.91 minutes
8.
15.4 minutes
9.
0.1346 min-1
10.
0.1210 min-1
11.
0.1514 min-1
12.
1634.6
13.
8.35 minutes
14.
59.2%
15.
No
1,2-Diethyl-3-hydroxpyridine-4-one
1.
15.22
2.
21.39
3.
36.62
4.
375.5
5.
988.2 mL
6.
352.3 mL
7.
0.341 hours
8.
1.824 hours
9.
0.724 h-1
10.
1.066 h-1
11.
0.62 h-1
12.
39.03
13.
1.016 hours
14.
55.4%
15.
No
2,2-dimethylaziridine
1.
102.7
2.
89.47
Basic Pharmacokinetics
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11-124
Multicompartment Modeling
3.
192.16
4.
1498.7
5.
15.78 L
6.
5.7 L
7.
1.695 minutes
8.
7.296 minutes
9.
0.148 min-1
10.
0.263 min-1
11.
0.093 min-1
12.
50.5
13.
4.65 minutes
14.
56.5%
15.
No
Flurbiprofen
1.
20.82
2.
329.6
3.
350.42
4.
7.42
5.
42.4 mL
6.
24.5 mL
7.
0.297 hours
8.
3.96 hours
9.
1.35 h-1
10.
0.303 h-1
11.
0.856 h-1
12.
106.18
13.
1.2 hours
14.
42.2%
15.
Yes
Furosemide
1.
0.304
2.
0.802
Basic Pharmacokinetics
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11-125
Multicompartment Modeling
3.
1.106
4.
19.88
5.
20.71 L
6.
7.67 L
7.
0.1005 hours
8.
0.722 hours
9.
2.55 h-1
10.
2.59 h-1
11.
2.71 h-1
12.
2.87
13.
0.322 hours
14.
62.99%
15.
No
Glycyrrhizin
1.
21.93
2.
162.56
3.
184.5
4.
29.8
5.
69.33 mL
6.
34.13 mL
7.
0.167 hours
8.
1.61 hours
9.
2.048 h-1
10.
0.873 h-1
11.
1.67 h-1
12.
161.13
13.
0.61 hours
14.
50.8%
15.
Yes
Human Deoxyribonuclease
1.
2235.78
2.
21384.3
Basic Pharmacokinetics
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11-126
Multicompartment Modeling
3.
23620.1
4.
11.01
5.
48.07 mL
6.
10.77 mL
7.
0.0805 hours
8.
3.027 hours
9.
1.929 h-1
10.
1.0223 h-1
11.
5.89 h-1
12.
24147
13.
0.433 hours
14.
28.9%
15.
Yes
40.24
2.
181.81
3.
222.05
4.
11.26
5.
20.62 mL
6.
11.6 mL
7.
2.89 h-1
8.
0.546 h-1
9.
1.625 h-1
10.
0.971 h-1
11.
0.839 h-1
12.
215.44
13.
0.711 hours
14.
43.8%
15.
Yes
Hydrocortisone
1.
32.8
2.
986.5
Basic Pharmacokinetics
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11-127
Multicompartment Modeling
3.
1019.3
4.
19.62
5.
44.1 mL
6.
23.01 mL
7.
0.053 hours
8.
1.56 hours
9.
6.838 h-1
10.
0.853 h-1
11.
5.85 h-1
12.
869
13.
0.267 hours
14.
47.8%
15.
Yes
Levodopa
1.
0.649
2.
2.61
3.
3.25
4.
15.37
5.
13.48 L
6.
4.31 L
7.
0.052 hours
8.
0.61 hours
9.
4.25 h-1
10.
3.56 h-1
11.
6.62 h-1
12.
11.6
13.
hours
14.
68.0%
15.
Yes
Meropenem
1.
11.35
2.
39.76
Basic Pharmacokinetics
REV. 99.4.25
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11-128
Multicompartment Modeling
3.
51.11
4.
9.78
5.
19.45 L
6.
12.20 L
7.
0.375 hours
8.
1.378 hours
9.
1.16 h-1
10.
0.802 h-1
11.
0.391 h-1
12.
41
13.
0.967 hours
14.
37.3%
15.
No
N-methylpyridinium-2-carbaldoxime chloride
1.
18.6
2.
3.106
3.
21.71
4.
12.9
5.
1.11 L
6.
6.77 L
7.
2.41 hours
8.
0.0598 hours
9.
1.752 h-1
10.
1.905 h-1
11.
8.218 h-1
12.
41.339
13.
0.327hours
?14.
45.5%
15.
Yes
Pyrazine Diazohydroxide
1.
41348.7
2.
46147.9
Basic Pharmacokinetics
REV. 99.4.25
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11-129
Multicompartment Modeling
3.
87496.6
4.
0.3744
5.
14.57 mL
6.
3.542 mL
7.
3.55 minutes
8.
26.97 minutes
9.
0.0474 min-1
10.
0.106 min-1
11.
0.0676 min-1
12.
9249
13.
11.97 minutes
14.
75.7%
15.
No
Terbinafene
1.
4692.8
2.
4594.6
3.
9287.4
4.
80.75
5.
3637.6 L
6.
300 L
7.
1.36 h
8.
31.2 h
9.
0.0421 h-1
10.
0.2692 h-1
11.
0.222 h-1
12.
2500
13.
6.42 hours
14.
91.8%
15.
No
Verrucarol
1.
3037.35
2.
57143.8
Basic Pharmacokinetics
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11-130
Multicompartment Modeling
3.
60181.1
4.
149.5
5.
15.81 L
6.
13.5 L
7.
16.7 minutes
8.
73.3 minutes
9.
0.0155 min-1
10.
0.0253 min-1
11.
0.0101 min-1
12.
666.63
13.
46.15 minutes
14.
28.1%
15.
Yes
Basic Pharmacokinetics
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11-131
CHAPTER 12
Protein Binding
OBJECTIVES
2.
Basic Pharmacokinetics
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12-1
CHAPTER 13
Nonlinear (Michaelis-Menton)
Kinetics
OBJECTIVES
1.
Given population average patient data, the student will devise (V) a dosage regimen which will maintain plasma concentrations of drug within the therapeutic
range.
2.
Given specific patient information, the patient will justify (VI) the optimal dosage
regimen.
3.
Given patient information regarding organ function, the student will devise (V)
and justify (VI) dosage regimens for the compromised patient.
4.
The student will write (V) a professional consult using the above calculations.
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13-1
13.1 Problems
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13-2
Cefadroxil
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 27)
AHFS 00:00.00
GPI: 0000000000
Sanchez-Pico, A., et al, "Nonlinear intestinal abosrption kinetics of cefadroxil in the rat", Journal of Pharmacy Pharmacology,
Vol.41, (1989), p. 179 - 185.
Cefadroxil is a cephalosporin antibiotic which is commonly used to treat various infections. It is usually given orally.
This study looks at the pharmacokinetics and bioavailability of cefadroxil in the rat.
PROBLEM TABLE 11 - 27. Cefadroxil
Dose
500 mg
7.31
1000 mg
14.67
Find .
Find the maximum clearance,, for this patient.
What would be the dose needed to acheive a steady-state concentration of 10 ?
You recommend changing the patient's dosage regimen to 300 mg/day. What would be your patient's steady state
plasma concentration?
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13-3
CD4
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 28)
AHFS 00:00.00
GPI: 0000000000
Qian, M., et al., "Pharmacokinetic evaluation of drug interactions with anti-human immunodeficiency virus drugs: V. effect of soluble CD4 on 2',3'-dideoxycytidine kinetics in monkeys", Drug Metabolism and Disposition, Vol. 20, (1992), p. 396 - 400.
2',3'-dideoxycytidine in combination with recombinant ST4 has been shown to be effective against HIV (human immunodeficiency virus) in vitro. This study examines whether or not the pharmacokinetics of 2',3'-dideoxycytidine are
affected by administration of CD4 (an immunoglobulin). Doses of each drug were given to male adult monkeys
weighing an average of 4.45 kg. The following data is for ST4 (soluble CD4).
PROBLEM TABLE 11 - 28. CD4
Dose
1.1 mg/kg
10.27
2.2 mg/kg
22.23
Weight of Monkey = 4.45 kg
Find .
Find the maximum clearance for this patient.
What would be the dose needed to acheive a steady-state concentration of 15 ?
You recommend changing the patient's dosage regimen to 1.5 mg/ kg. What would be your patient's plasma concentration?
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13-4
Methylprednisone
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 29)
AHFS 00:00.00
GPI: 0000000000
Haughey, D, and Jusko W.., "Bioavailability and nonlinear dispositionof methylprednisolone and methylprednisone in the rat",
Journal of Pharmaceutical Sceicnes, Vol. 81, (1992), p. 117 - 121.
Methylprednisone is a corticosteroid which is commonly used in the treatment of medical emergencies such as cardiovascular shock, asthma, and cerebral edema. The following data was obtained for two methylprednisolone doses. The
plasma concentration measurement given for each dose below is that for the central compartment.
PROBLEM TABLE 11 - 29. Methylprednisone
Dose
10 mg
6834
50 mg
71519
Find .
Find the maximum clearance for this patient.
What would be the dose needed to acheive a steady-state concentration of 10,000 ?
You recommend changing the patient's dosage regimen to 30 mg. What would be your patient's plasma concentration?
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13-5
Mezlocillin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 30)
AHFS 00:00.00
GPI: 0000000000
Jungbluth, G. and Jusko, W., "Dose-dependent pharmacokinetics of mezlocillin in rats", Antimicrobial Agents and Chemotherapy,
Vol. 33, (1989), p. 839 - 843.
Mezlocillin is an antibiotic used to treat various types of infection. It is usually given by the intravenous route and
exhibits dose-dependent (nonlinear) pharmacokinetics. This article compares two intravenous bolus doses, one of 20
mg/kg and one of 200 mg/kg in rats. The following data was calculated from the results of this study.
PROBLEM TABLE 11 - 30. Mezlocillin
Dose
20 mg/kg
158.6
200 mg/kg
294.1
Rat weight = 425 g
Find .
Find the maximum clearance,, for this patient.
What would be the dose needed to acheive a steady-state concentration of
200 ?
You recommend changing the patient's dosage regimen to 150 mg/ kg. What would be your patient's plasma concentration?
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13-6
Naphthol
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 31)
AHFS 00:00.00
GPI: 0000000000
Redegeld, A., Hofman, G., and Noordhoek, J., "Conjugative clearance of 1-naphthol and disposition of its glucuronide and sulfate
conjugates in the isolated perfused rat", Journal of Harmacology and Experimental Therapeutics, Vol. 244, (1988), p. 263 - 267.
1-naphthol is a small phenolic compound which is extensively metabolized by conjugation. This study looks at the
pharmacokinetics of naphthol in a rat.
PROBLEM TABLE 11 - 31. Naphthol
Dose
30 mol
6.79 M
40 mol
8.63 M
Find .
Find the maximum clearance,, for this patient.
What would be the dose needed to acheive a steady-state concentration of 7.7 M?
You recommend changing the patient's dosage regimen to 35 mol. What would be your patient's plasma
concentration?
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13-7
Paroxetine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 32)
AHFS 00:00.00
GPI: 0000000000
Sindrug, S., Brosen, K, and Gram, L.., "Pharmacokinetics of the selective serotonin reuptake inhibitor paroxetine: nonlinearity
and relation to the sprateine oxidation polymorphism", Clinical Pharmacology and Therapeutics, Vol. 51, (1992), p. 288 - 295.
Paroxetine hydrochloride (Paxil) is a selective serotonin reuptake inhibitor which is used in the treatment of
depression. Paroxetine is metabolized both by oxidation and conjugation with the conjugated metabolites
excreted in the urine. Paroxetine exhibits dose-dependent (nonlinear) pharmacokinetics. The following
data is for a male diabetic patient who was concurrently taking insulin.
PROBLEM TABLE 11 - 32. Paroxetine
Dose
10 mg daily
1.65
20 mg daily
3.30
30 mg daily
8.25
40 mg daily
13.20
50 mg daily
26.40
60 mg daily
39.60
70 mg daily
66.00
Find .
Find the maximum clearance,, for this patient.
What would be the dose needed to acheive a steady-state concentration of 50 ?
You recommend changing the patient's dosage regimen to 36 mg/day. What would be your patient's plasma concentration?
Basic Pharmacokinetics
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13-8
Phenytoin
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 33)
AHFS 00:00.00
GPI: 0000000000
Levine, M., et al., "Evaluation of serum phanyton monitoring in an acute care setting", Therapeutic Drug Monitoring, Vol. 10,
(1988)., p. 50 - 57.
Phenytoin is an agent which is commonly used in the treatment of epilepsy. This drug exhibits nonlinear kinetics.
Phenytoin is mainly eliminated from the body by hepatic cytochrome P-450 metabolism. Several doses of phenytoin
were studied in patients and the data is summarized below:
PROBLEM TABLE 11 - 33.
Phenytoin
Dose
Day
300 mg at bedtime
5.0
12
11.4
49
21.5
(started on day 1)
200 mg BID
(started on day 6)
200 mg BID
(started on day 6)
Find .
Find the maximum clearance,, for this patient.
What would be the dose needed to acheive a steady-state concentration of
15 ?
You recommend changing the patient's dosage regimen to 300 mg/day. What would be your patient's plasma concentration?
Basic Pharmacokinetics
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13-9
(Problem 11 - 34)
AHFS 00:00.00
GPI: 0000000000
Boucher, B. et al., "Phenytoin pharmacokinetics in critically ill trauma patients", Clinical Pharmacology and Therapeutics, Vol.
44, (1988)., p. 675 - 683.
Phenytoin is an agent which is commonly used in the treatment of epilepsy. This drug exhibits nonlinear kinetics. This
study looks at several doses of phenytoin in severely ill trauma patients. The data given below is that obtained for one
male, 25 year-old, patient who weighed 85 kg.
PROBLEM TABLE 11 - 34. Phenytoin
Dose
615 mg/ day
10
588 mg/day
8.5
Find .
Find the maximum clearance,, for this patient.
What would be the dose needed to acheive a steady-state concentration of 12?
You recommend changing the patient's dosage regimen to 450 mg/ day. What would be your patient's steady-state
plasma concentration?
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13-10
Phenytoin in Pediatrics
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 35)
AHFS 00:00.00
GPI: 0000000000
Bauer, L. and Blouin, R., "Phenytoin Michaelis-Menten pharmacokinetics in caucasian paediatric patients", Clinical Pharmacokinetics, Vol. 8, (1989)., p. 545 - 549.
Phenytoin is an agent which is commonly used in the treatment of epilepsy. This drug exhibits nonlinear kinetics. This
study looks at several doses of phenytoin in pediatric patients of several ages. The data for the 4 to 6 year old patients
is given below.
Dose
7.5 mg/ kg/ day
15
10
Find .
Find the maximum clearance,, for this patient.
What would be the dose needed to acheive a steady-state concentration of
12 ?
You recommend changing the patient's dosage regimen to 4.5 mg/ kg/ day. What would be your patient's steady-state
plasma concentration?
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13-11
Quinalapril
(Problem 11 - 36)
AHFS 00:00.00
GPI: 0000000000
Elliott, H., et al., "Dose responses and pharmaockinetics for the angiotensin converting enzyme inhibitor, quinapril", Clinical
Pharmacology and Therapeutics, Vol. 52, (1992), p. 260 - 265.
Quinalapril is an angiotensin converting enzyme (ACE) inhibitor which is used in the treatment of hypertension and
heart failure. The optimal dosage regimen for the ACE inhibitors is controversial and this study further investigates
quinalapril's pharmacokinetics at various doses ranging from 0.5 to 20 mg. Quinalapril is a prodrug which is metabolized to its active form, quinalaprilat.
Dose
(of quinalapril)
(of quinalaprilat)
2.5 mg daily
47.5
5.0 mg daily
98.1
Find .
Find the maximum clearance,, for this patient.
What would be the dose needed to acheive a steady-state concentration of
75 ?
You recommend changing the patient's dosage regimen to 3.0 mg/day. What would be your patient's plasma concentration?
Basic Pharmacokinetics
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13-12
Vanoxerine
Problem Submitted By: Maya Leicht
Problem Reviewed By: Vicki Long
(Problem 11 - 37)
AHFS 00:00.00
GPI: 0000000000
Ingwersen, S., et al., "Nonlinear multiple-dose pharmacokinetis of the dopamine reuptake inhibitor vanoxerine", Journal of Pharmaceutical Sciences, Vol. 82, (1993)., p. 1164 - 1166.
Vanoxerine is a pre-synaptic dopamine reuptake inhibitor which may be useful as an antidepressant. The bioavailability of vanoxerine is changed by food intake. The bioavailability after fasting is increased 76% by a low-fat meal and
255% by a high-fat meal. In this study, the volunteers were given doses of vanoxerine after eating a standard breakfast
of one bowl of cereal with milk, two slices of toast with sunflower margarine and jam, and one cup of tea.
Dose
25 mg
3.4
75 mg
15.1
125 mg
46.5
Find .
Find the maximum clearance,, for this patient.
What would be the dose needed to acheive a steady-state concentration of
30.0 ?
You recommend changing the patient's dosage regimen to 100 mg. What would be your patient's plasma concentration?
Basic Pharmacokinetics
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13-13
13.2.1
ANSWERS
Cefadroxil
2144.75
147.2 g/day
683.14 mg
4.38
CD4
135.09
69.28 mg/day
6.92 mg/day
14.4
Methylprednisone
Basic Pharmacokinetics
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13-14
52345.27
86.60 mg/day
13.89 mg/day
27747.1
Mezlocillin
324.95
25.92 mg/day
68.23 mg/day
1676.04
Naphthol
46.14 (M
233.86 (mol
25.61 (mol
43.5 (M
Paroxetine
4.125
45 mg/day
41.6 mg/day
16.5
Phenytoin
4.014
540.85 mg/day
426.7 mg/day
5
Phenytoin in the Critically Ill
3.517
831.3 mg/day
642.88 mg/day
4.15
Phenytoin in Pediatrics
6.67
162.5 mg/day
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13-15
104.46 mg/day
4.74
Quinalapril
1503.15
81.61 mg/day
3.88 mg/day
57.36
Vanoxerine
20.96
179.08 mg/day
105.4 mg/day
26.5
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13-16
CHAPTER 14
ORGANIZATION
Following are several exams which have been used
in previous classes. These exams cover Chapters 1
through 4. Answers (including the graphs) are
included in a format similar to real exam conditions,
and some exams have the problems worked out
completely.
You are encouraged to work out the exams under
conditions similar to how you will take the exam.
You will want to have a calculator, semi-log graph
paper, and scratch paper available. Before you
begin to answer the questions, you will want to: 1)
create the model from the description of the drugs
pharmacokinetics, 2) graph all of the data as discussed in the chapters. From these graphs the
answers will become available. Your graphs should
look like the graphs included in the answers. Applicable equations vary by exam and are included at the
beginning of each chapter covered by the exam.
Remember where you are in the course: Learn the
tools; get the pharmacokinetic parameters from
patient information. So in this section you must be
able to analyze pharmacokinetic data and extract the
pharmacokinetic parameters. That means: Assess
the pharmacokinetic description of the drug and creBasic Pharmacokinetics
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14-1
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14-2
14.1.1
NIFEDIPINE DATA
Nifedipine (Procardia ) is a calcium channel blocker which specifically inhibits potential-dependent channels not
receptor-operated channels, preventing calcium influx of cardiac and vascular smooth muscle (coronary, cerebral).
Calcium channel blockers reduce myocardial contractility and A-V node conduction by reducing the slow inward calcium current. They are indicated in angina, cardiac dysrhythmias, and hypertension among others. Nifedipine
appears to be metabolized entirely into an inactive metabolite, an acid and subsequently further metabolized to a lactone. Both the acid and the lactone are excreted into the urine and the feces.
PROBLEM TABLE 11 - 1.
Pharmacological Data
Fall in Diastolic
BP
Cp (ng/mL)
Time (hr)
Fall in Diastolic
BP
15
13.0
10
40
12.3
12
100
10.7
13
200
10.0
7.0
Echizen and Eichelbaum (Clin Pkin 1986; 11:425-49) and Kleinbloesem et al (Clin Pcol Therap 1986; 40: 21-8)
reviewed the pharmacokinetics of Nifedipine. While the drug is not routinely given by IV bolus and does not strictly
conform to a one compartment model, let's treat the data as if those problems can be ignored. The following data is
offered for evaluation:
PROBLEM TABLE 11 - 1. Nifedipine
IV Bolus Profile
Cp
(mcg/L)
Xm1f
(mg)
Xm1u
(mg)
Time (hr)
Cm1
(mcg/L)
0.5
24.7
44.4
139
71.8
.14
.59
65.6
96.5
.44
1.83
Xm2f
(mg)
Xm2u
(mg)
.028
.11
31.1
100
.77
3.25
.073
.29
14.6
94.7
1.1
4.65
.135
.54
12
76.5
1.69
7.10
.291
1.15
24
34
2.77
11.63
.75
2.95
3.6
15.1
1.3
5.0
7 days
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14-3
14.1.2
NIFEDIPINE QUESTIONS
1) dR/dT = slope of the Pharmacological
response vs. time profile (mmHg/hr)
2) dR/d(lnC) = slope of the Pharmacological response vs concentration profile
(mmHg)
21) Xm1inf = Mass of the acidic metabolite in the body at infinite time. (mg)
Im1 = Intercept of the acidic metabolite concentration vs time profile = 181.2 mic/L
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14-4
Answer Pool Any number from the answer pool may be used
Small Numbers
Big Numbers
-0.0001
13
-0.0010
0.010
15.1
-0.0100
0.018
17
-0.0180
0.028
20
-0.0280
0.042
25
-0.0375
0.070
38.9
-0.0750
0.085
50
-0.0850
0.110
85
-0.110
0.138
170
-0.138
0.375
181.2
-0.375
0.750
295
-0.750
1.30
415
-1.30
1.85
434
-1.85
2.0
787
-2.0
2.67
2100
-2.67
3.6
3570
-3.6
5.0
8500
-5.0
7.5
21000
-7.5
8.5
35700
-10
9.9
85000
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14-5
14.1.3
NIFEDIPINE SOLUTIONS
X
km1
Xmf1
Xm1
kmf1
kmu1
Xmu1
kmu2
Xmu2
km2
Xmf2
Xm2
kmf2
Graph #2
Graph #1
- 0.75 mmHg/hr
R vs T
Nifedipine
14
14
13
13
RESPONSE (MMHG)
12
Response (mmHg)
12
11
10
11
10
2 mm Hg
9
8
7
6
0
101
102
103
Concentration (ng/mL)
Graph #4
Nifedipine IV Bolus
10
/mL)
L)
Graph #3
Time (hr)
103
103
CONCENTRATION MIC/L
CONCENTRATION MIC/L
100
102
1.85 hr
50
101
2
102
10 hrs
101
Time (hours)
12
16
20
24
Time (hours)
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14-6
dR
------- = 0.75mmHg hr
dT
1.
dR
------------ = 2.0mmHg
d ln C
2.
dR
------0.75 = 0.375hr 1
dT - = ------------d-----------ln C = -----------2
dR
dT
-----------d ln C
3.
Answer
#1------------------------Answer #2
4.
kr = 0, Nifedipine is not excreted into the urine, it is metabolized entirely K1 = k m1 from pkin description
5.
6.
7.
0.693
1.85hr
from graph #3
from graph #3
8.
9.
10.
11.
12.
13.
14.
15.
Cp 1 + Cp 2
Cp 2 + Cp 3
Cp 3 + Cp last
Cp last
Cp o + Cp 1
------------------------- t 1 + ------------------------- t2 + ------------------------- t 3 + ------------------------------ t last + --------------
2
2
2
2
K1
+ 139- 2 + 139
+ 65.6 2 + 65.6
+ 31.1- 2 + 31.1
+ 14.6- 2 + ------------14.6 mcg
295
----------------------------------------------------------------------------------------------------------hr
2
2
2
2
0.375 L
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14-7
16
17.
18
Cp o + Cp 1
-------------------------- t =
2
Cp L 14.6
---------- = ------------- = 38.9mic L hr
k
0.375
AUMC = AUC MRT = 787 2.67 = 2100mic L hr
T1 C p1 + T 2 C p 2
T2 C p2 + T3 C p3
T 3 C p 3 + T last C p last
T last C p last Cp last
T 0 C p o + T1 C p1
---------------------------------------------- t 1 + ---------------------------------------------- t 2 + ---------------------------------------------- t 3 + --------------------------------------------------------- t last + ------------------------------ + ---------------
2
2
2
2
2
K1
K1
0 295 + 2 139
2 139 + 4 65.6
4 65.6 + 6 31.1
6 31.1 + 8 14.6
8 14.6
14.6 mcg 2
--------------------------------------- 2 + ---------------------------------------- 2 + ------------------------------------------ 2 + ------------------------------------------ 2 + ------------------ + ---------------- ----------hr
2
2
2
2
2
0.375
0.375 L
mcg 2
{ 278 + 540.4 + 449 + 303.4 + 311.47 + 103.82 } = 1986.1----------hr
L
19.
MRT IV
1
MRT iv = --- = 2.67hr estimate. Using trapazoidal rule and definitions
k
mcg 2
mcg 2
1986.1----------hr
AUMC est 2100 ----------hr
AUMC trap
L
L
= --------------------------- = ------------------------------------ = 2.42 hr ------------------------ = ------------------------------- = 2.67 hr
mcg
mcg
AUC est
AUC trap
787 ----------hr
821.9----------hr
L
L
20.
21.
22.
Vm1 = 170L
k m1 X 0
K2t
K1t
Cp m = --------------------------------------- {e
e
}
( K1 K2 ) V dm
m1
0
- .
the intercept, I, given as 181.2 mic/L in the data = ---------------------------------------
( K1 K2 ) V dm
Thus
k m1 X 0
0.375 25mg
V dm = ----------------------------------------------------= ---------------------------------------------------------------- = 169.6 L
mic
mg
( K1 K2 ) 181.2--------( 0.375 0.07 ) 0.1812------L
L
23.
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14-8
24.
Data
Cpm ( n ) + Cpm ( n + 1 )
-------------------------------------------------------2
T ( n )
AUC
AUC
t
0
Time (hr)
Cpm (mcg/L)
0.5
24.7
0 + 24.7
------------------2
0.5
6.175
6.175
44.4
24.7 + 44.4
--------------------------2
0.5
17.275
23.45
71.8
44.4 + 71.8
--------------------------2
58.1
81.55
96.5
71.8 + 96.5
--------------------------2
168.3
249.85
100
96.5 + 100
------------------------2
196.5
446.35
94.7
100 + 94.7
------------------------2
194.7
641.05
12
76.5
94.7 + 76.5
--------------------------2
342.4
983.45
24
34
76.5 + 34
---------------------2
12
663
1646.45
Cpm last
+ ------------------K small
485.7
2132.15
25.
26.
27.
28.
29.
k m1u = 0.042hr
30.
k m1f = 0.01hr
31.
k m2 = 0.018hr
k m1u Xm1u
k m1u
----------- = ------------ = -------------------= 15.1mg
-----------------
1
K2
Xo
25mg
0.07hr
k m1f X m1f
k m1f
---------- = ----------- = -------------------= 3.6mg
--------------1
K2
Xo
25mg
0.07hr
0.07 hr
trap
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+ 0.042 hr
+ k m2
14-9
32.
K2 = 0.07hr
From your LaPlace Transforms, you know that the equation is bi-exponential, with one of
the slopes being K1 and the other being K2. The terminal slope of graph #4 is 0.07 hr -1, which is not K1 (0.375 hr -1).
So it must be K2.
33.
34.
35.
36.
37.
38.
39.
k m2u = 0.11hr
40.
k m2f = 0.028hr
k m2u
k m2u
X m2u
5.0mg
----------------------- = ----------------------------= ---------= -----------------------------------1
K3
X m2u + Xm2f
5.0mg + 1.3mg
0.138hr
k m2f
k m2f
Xm2f
1.3mg ----------------------= --------- = ----------------------------= -----------------------------------1
K3
X
+
X
5.0mg
+ 1.3mg
m2u
m2f
0.138hr
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14-10
14.2.1
ENALAPRIL DATA
Enalapril (Vasotec ) is an angiotensin converting enzyme (ACE) Inhibitor effective in the treatment of hypertension
and chronic heart failure (CHF). The parent compound is weakly active, while its sole metabolite, Enalaprilat, exhibits almost all of the pharmacological activity. Original work on the pharmacokinetics of Enalapril showed the parent
drug, Enalapril and its metabolite, Enalaprilat, show up in both feces and urine.
The following data was offered regarding the Pharmacological response of Enalaprilat as judged by the fall in Seated
Systolic Blood Pressure (SSBP).
PROBLEM TABLE 11 - 1. Enalapril
Fall in SSBP
(mmHg)
Dose (mg)
Fall in SSBP
(mmHg)
15
12
10
10
10
8.6
12
15
10
18
20
16
24
25
20
30
24
Cpm
(ng/ml)
Cumulative
Enalapril in
urine (mg)
Cumulative
Enalapril
in feces
(mg)
Time
(hr)
Cp
(ng/mL)
29
7.5
0.41
0.12
17
11.6
0.65
0.20
10
13.8
0.80
0.24
5.9
14.9
0.88
0.26
15.2
0.96
0.30
1.0
0.3
14.7
10
13.8
20
9.8
30
6.9
40
4.9
50
3.4
Cumulative
Enalaprilat
in urine
(mg)
Cumulative
Enalaprilat
in feces
(mg)
2.25
1.45
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14-11
The intercept of Cp m vs t was found to be 19.8 ng mL and a total of 2.25 mg of enalaprilat was found in the
urine while 1.45 mg was found in the feces.
PROBLEM TABLE 11 - 1. Enalapril
Answer Pool
Negative
Numbers
Small
Numbers
Small
Numbers
Medium
Numbers
Large
Numbers
0.000
0.014
1.00
14.5
100
-0.014
0.021
1.45
19.8
174
-0.021
0.030
.1.90
30.3
528
-0.030
0.035
2.25
33.0
395
-0.035
0.039
3.75
37.5
693
-0.110
0.110
5.00
39.5
834
-0.390
0.150
6.93
50.0
1740
-0.530
0.300
8.00
70.0
5280
-0.700
0.390
9.00
94.0
14400
-0.900
0.530
9.76
97.0
16000
k mu k m Xo 1 e K2t 1 e K1t
------------------------ --------------------- --------------------( K1 K2 )
K2
K2
( k mf k m Xo ) 1 e K2t 1 e K1t
------------------------ --------------------- --------------------( K1 K2 )
K2
K1
km X 0
K2t
K1t
---------------------------------------
) (e )
( K1 K2 ) Vd m ( e
D.
k mu k m Xo
K2t
K1t
------------------------
) (e )
( K1 K2 ) ( e
km X 0
K2t
K1t
------------------------
) (e )
( K1 K2 ) ( e
K1t
kr X 0 e
k
K1t
------u- X0 ( 1 e
)
K1
X 0 K1t
------ e
V
k
K1t
------f- X0 ( 1 e
)
K1
X0e
K1t
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14-12
14.2.2
ENALAPRIL QUESTIONS
Find the equation for:
1) X, the mass of parent drug, Enalapril, in
the body.
2) Xu, the mass of parent drug, Enalapril,
in urine.
3) dX u/dt, the rate of excretion of parent
drug, Enalapril, in urine.
4) Xf, the mass of parent drug, Enalapril, in
feces.
5) Xm, the mass of metabolite, Enalaprilat,
in the body.
6) Xmu, the mass of metabolite, Enalaprilat, in urine.
7) dXmu/dt, the rate of excretion of metabolite, Enalaprilat, in urine.
8) Xmf, the mass of metabolite, Enalaprilat, in feces.
9) Cp, the plasma concentration of parent
drug, Enalapril.
10) Cpm, the plasma concentration of
metabolite, Enalaprilat.
13) d(ln(C))/dT
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36) dXmu/dt vs T
49) XMU0
37) T*Cp vs T
50) XMF0
38) T*Cpm vs T
51) X
52) X u
39) AUC(enalapril)
40) AUMC(enalapril)
53) X f
41) MRT(enalapril)
54) X m
42) AUC(enalaprilat)
55) X mu
43) AUMC(enalaprilat)
56) X mf
44) MRT(enalaprilat)
57) Cp0
45) X0
58) Cpm0
46) XU0
59) Vd
47) XF0
60) Vdm
48) XM0
14.2.3
ENALAPRIL SOLUTIONS
Enalapril Model
kf
Xf
kr
Xu
km
Xmf
kmf
Xm
kmu
Xmu
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sponse
esponse
RESPONSE DATA
R vs C
24
22
20
18
16
14
12
10
10
10
R vs T
15
14
13
12
11
10
9
8
2
Concentration
10
12
Time (hr)
Enalapril
101
101
Concentration (ng/mL)
Concentration (ng/mL)
102
100
0
100
0
Time (hrs)
10
20
30
40
50
Time (hours)
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k1t
X = Xoe
k
k1t
X u = ----r- X o ( 1 e
)
k1
dx u dt = k r Xo e
10
k1t
k
k1t
)
X f = -----f Xo ( 1 e
k1
km X o
k2t
k1t
Xm = --------------------( e
e
)
( k1 k2 )
k mu k m Xo 1 e k2t 1 e k1t
Xmu = ---------------------------------------- -------------------( k1 k2 )
k2
k1
dX mu k mu k m Xo k2t k1t
------------- = --------------------- ( e
e
)
dt
k1 k2
( k mf k m X ) 1 e K2t 1 e K1t
o
X mf = ------------------------ --------------------- --------------------K1 K2
K2
K1
C p = C po e
k1t
D- e k1t
= -----Vd
km X 0
K2t
K1t
-
Cp m = --------------------------------------) (e
)
( K1 K2 ) Vd m ( e
11
dR dt = 0.7
12
dR d ( ln c ) = 20
13
d ( ln c )
0.7 = 0.035
dt = ---------20
14
Xu
1
k r = ------ k 1 = 1--- 53 = 0.106 = 0.11hr
5
Xo
15
Xf
1
k f = ------ k 1 = 0.3
------- 0.53 = 0.0318 = 0.03 hr
Xo
5
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16
Xmu + X mf
1
2.25 + 1.45
k m = ----------------------- k 1 = --------------------------- 0.53 = 0.39 hr
Xo
5
17
Xmu
1
2.25
k 2 = ---------- 0.035 = 0.21hr
k mu = -----------------------
3.7
Xmu + Xmf
Xmf
1
1
1.45
k 2 = ---------- 0.035hr = 0.014 hr
k mf = -----------------------
3.7
Xmu + Xmf
18
19
K1 = 0.53hr
20
K2 = 0.035hr
= slope of Cp vs T = k m + kf
Cp ( 0 ) = 50ng mL
21
22
I = 19.8 ng mL
23
dX
--------u- vs T
dt
I = 0.53
k f X0 = ( 0.03 5 ) = 0.15ng mL
24
PROBLEM TABLE 11 - 1.
T mid
Time
Xu
Xu
Xu
---------T
Xu
---------T
0.5
0.41
0.41
0.41 1
0.41
1.5
0.65
0.24
0.24 1
0.24
2.5
0.80
0.15
0.15 1
0.15
3.5
0.88
0.08
0.08 1
0.08
0.96
0.08
0.08 2
0.04
25
0.53 hr
26
0.035 hr
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14-17
44
16000
--------------- = 30.3hr
528
45
X 0 = 5mg
29 )- 1 = 39.5ng mL hr
---------------------2
46
Xu ( 0) = 0
47
Xf ( 0 ) = 0
(0 +
48
Xm ( 0 ) = 0
49
Xmu ( 0 ) = 0
27
0.53 hr
28
0.53 hr
29
( 50 +
30
7.5 ) 1 = 3.75ng mL hr
--------------------2
31
2
---------- = 3.77ng mL hr
0.53
50
Xmf ( 0 ) = 0
32
3.4 - = 97ng mL hr
-----------0.035
51
X = 0
52
Xu = 1mg
33
94 ng mL hr
53
34
1 19.8 -----------0.035
1 - = 528ng mL hr
--------0.53
35
dX
AUC --------u- vsT = 1mg
dt
36
dX mu
AUC ------------ vsT = 2.25mg
dt
37
174 ng mL hr
38
16000 ng mL hr
39
94 ng mL hr
54
Xm = 0
55
X mu = 2.25mg
56
X mf = 1.45mg
57
Cp 0 = 50ng mL
58
Cp m ( 0 ) = 19.8ng mL
dose- = 100L
Vd = -----------Cp ( 0 )
59
2
40
174 ng mL hr
41
1.9 hr
42
528 ng mL hr
43
16000 ng mL hr
60
( km X0 )
( 0.39 5
)
Vd m = --------------------------= ----------------------------------------------------( K1 K2 ) I ( K1 K2 ) ( 0.0198
2
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CIPROFLOXACIN DATA
Ciprofloxacin (Cipro ) is a fluoroquinolone, synthetic broad spectrum antibacterial agent. It is reasonably well
absorbed orally and is excreted into the urine and is metabolized to four known metabolites which are also excreted
into the urine. Before an accurate analytical assay was worked out for ciprofloxacin, a microbiological assay was used
to determine the pharmacokinetics. This assay utilized the ability of ciprofloxacin to kill microorganisms grown on an
agar plate and create a clear zone of no growth, the zone of inhibition. The following data was collected from that procedure: (Intercept for the extrapolated metabolite graph was 0.372 mg/L)
PROBLEM TABLE 11 - 1.
Pharmacological Response
Zone -mm
Time (hrs)
Pharmacological Response
zone - mm
27
4.7
0.01
23.2
13.5
0.05
20.4
17.3
0.1
18.5
10
19.5
0.15
5.2
24
21
0.2
23.5
0.3
28
0.7
Time
(Hrs)
Cp
(mg/L)
0.5
Cpm
(mg/L)
Interval
(hours)
Cipro (mg)
in urine
0.045
0-4
184
0.077
4-8
92
2.53
0.115
8 - 12
46
2.12
0.129
1.79
0.128
0.119
1.26
0.108
0.893
0.084
10
0.062
12
0.045
16
0.023
18
0.016
20
0.012
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14-19
14.3.2
CIPROFLOXACIN QUESTIONS
13) Xuinf
14) Xminf
(Cipro)(hr)
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14.3.3
CIPROFLOXACIN SOLUTIONS
Ciprofloxacin Model
X
ku
Xu
kmu
Xmu
km
Xm
Ciprofloxacin
Ciprofloxacin
30
20
15
10
5
0
5
10
15
20
25
Time (hr)
100
100
10-1
10 -1
10-2
4
Time (hours)
10 0
Concentration (mic/mL)
Concentration (mic.mL)
10 -1
101
10 -2
10
15
20
dXu/dt (mg)
Ciprofloxacin
Concentration (mic/mL)
25
30
25
20
15
10
5
0
101
Time (hours)
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Tmid (hours)
14-21
K = 0.173hr
1.
2.
R
hr- = 0.13hr 1
k r = -----0- = 65.13mg
-----------------------------X0
500mg
1
k m = 0.043hr
k mu = 0.462hr
Cp 0 = 3.57mic mL
Vd = 140L
Vd m = 200L
9.
AUMC = 119.7mic mL hr
10
MRT = 5.8hr
11
dX u
AUC = 375mg ---------vs
( t mid )
dt
X = 0
13
X u = 375mg
14
Xm = 0
16
T 1 2 = 4.0hr
17
Cl = 24.2L hr
18
dR
------- = 0.95mm hr
dT
19
dR = 5.5mm
----------------d ( ln C )
20
d----------------( ln C ) = 0.173hr 1
dt
21
Slope of Cp vs T = 0.173
22
Slope
of
dX u
--------- vs ( t mid ) = 0.173
dt
23
Cp m vsT = 0.173
24
Cp m vsT = 0.462
25
k mu k m X 0
Kt
kmut
---------------------------- (e e
)
( k mu K )
12
X mu = 125mg
AUC = 20.7mic mL hr
8
Cp vs T
15
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14.4.1
METHYLPHENIDATE DATA
Methylphenidate (MP) (Ritalin) is an effective stimulant in the treatment of narcolepsy in adults and attention deficit
syndrome in children. It is entirely metabolized to the inactive metabolite, Ritalinic Acid (RA), by the liver which is
subsequently excreted unchanged into the urine. Pharmacological response was measured objectively using sleep
latency as measured by encephalography. Sleep latency is the time required to fall asleep in a darkened quiet room.
PROBLEM TABLE 11 - 1.
Response (min)
Cp (mcg/mL)
Response (min)
0.5
22
22.5
16
18
1.5
10
15
10
Profiles
(Intercept of extrapolated RA line 0.21
mic/mL)
Plasma Vs. Time Profile
10 mg MP given by IV Bolus
Time (hr)
Cp (MP)
(mcg/mL)
Cpm (RA)
(mcg/mL
0.5
0.091
0.022
0.067
0.029
1.5
0.049
0.030
0.035
0.028
2.5
0.026
0.024
0.019
0.020
0.010
0.012
0.003
0.004
-------
0.0013
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14.4.2
METHYLPHENIDATE QUESTIONS:
From the above information find the pharmacokinetic parameters:
1) K (elimination rate constant of MP) (hr
-1
6) Vd (MP)(L.)
7) Vdm (RA)(L.)
8) AUC (Cp vs t for MP by IV bolus) (mic/
mL * hr)
9) AUMC (t*Cp vs t for MP by IV bolus
(mic/mL * hr2)
19) Xuinf
20) Xminf
21) T1/2
(MP)(hr)
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14.4.3
METHYLPHENIDATE SOLUTIONS
X
km
Xm
kmu
Xmu
R vs C
Methyl Phenidate
24
Response
25
20
22
20
0
18
15
Response (min)
16
10
14
12
5
10
0.5
1.0
1.5
10
2.0
10
Concentration
Time (hr)
MP IV Bolus - Metab
100
100
10-1
10-1
Concentration (mic/mL)
Concentration (mic/mL)
10-2
0
Time (hours)
10-2
0
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Time (hours)
14-25
K = 0.63hr
kr = 0
k m = 0.63hr
k mu = 0.90hr
Cp 0 = 0.125mic mL
6
pool)
pool)
AUC = 0.20mic mL hr
T 1 2 = 1.1hr
22
Cl = 50.4L hr
23
dR
------- = 11.4min hr
dT
24
dR - = 17.5 min
-------------------d ( ln Cp )
25
d-------------------( ln Cp )- = 0.63hr 1
dT
21
26
27
Cp = Cp 0 e
28
9.
AUMC = 0.315mic mL hr
10
MRT = 1.57hr
29
dX mu
k mu k m X0 K1t
(e
e
------------- vsT mid = ----------------------------( K2 K1 )
dT
30
X0 = 10mg
14
Xm ( o ) = 0
15
Xmu ( 0 ) = 0
32
16
0.79
31
km X0
K1t
Cp m vsT ( RA ) = ------------------------(e
e
( K2 K1 )
pool)
pool)
33
34
X = 0
19
Xu = 0
20
Xm = 0
km X0
Xm = --------------------------------------------( s + K1 ) ( s + K2 )
The equation for
km X 0
K1t
K 2t
Xm = ------------------------(e
e
)
( K2 K1 )
18
13
17
k t
dX mu
------------ vsT mid = 0.63
dT
11
AUC = 0 MP is not excreted in
the urine
12
AUC = 10mg All of RA is
excreted in the urine
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14.5.1
ADINAZOLAM DATA
Adinazolam (AD) is a triazolobenzodiazepine prodrug which has been shown to have antidepressant activity through
its metabolite, N-desmethyladinazolam (NDMAD). Both AD and NDMAD are excreted into the urine. The following
data regarding AD and NDMAD was collected from the works cited. AD appears to interfere with mental ability. One
of the tests was the ability to Substitute Digits for Symbols (DSST) and the interference of that process was the
response measured below:
PROBLEM TABLE 11 - 1.
Pharmacological Response
% Pharm Response
Time (hrs)
% Pharm Response
59.7
33
200
45.3
48
300
29.5
59
400
15.5
68
500
12
74
600
Five mg IV bolus dose of AD yieled: (intercept of extrapolated metabolite line is 150 ng/mL)
Plasma Data
Urine Data
Time
(hr)
Cp (AD)
(ng/mL)
0.5
47
40
15.4
28
3
4
14.7
5
6
Cpm(NDMAD)
(ng/mL)
Time (mid)
t
AD Ecretion Rate
(mg/hr)
0.5
0.56
0.48
23.5
0.34
27.3
0.18
28
0.09
27
7.5
24.9
20
10
15
12
11
15
7.5
18
4.2
20
2.8
22
1.9
24
1.2
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14.5.2
ADINAZOLAM QUESTIONS
13) Xuinf
14) Xminf
(AD)(hr)
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Pool
Numbers
LaPlace Forms
-1.33
-0.1
10
100
Xo/(s+K)
-1.55
-0.133
0.1
1.33
12.5
120
Xo/(s+km)
-2
-0.15
0.133
1.5
20
167
Xo/(s+kmu)
-3.33
-0.2
0.15
30
200
km * Xo / ((s+km) * (s+kmu))
-4
-0.333
0.2
37.5
375
-5
-0.5
0.333
40
425
km * Xo / ((s+km) * (s+K ))
-6.93
-0.693
0.5
50
500
-7.5
-0.73
0.693
55.6
630
km * Xo / ((s+K ) * (s+kmu))
-8.25
-0.85
0.75
6.67
66.7
775
-9
-0.95
0.84
7.5
75
930
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14.5.3
ADINAZOLAM SOLUTIONS
ku
Xu
kmu
Xmu
km
Xm
onse %
R vs T
60
Adinazolam metabolite
80
50
70
40
Response (%P-col)
60
30
20
10
2
Time (hr)
50
40
30
10 2
10 3
Concentration (ng.mL)
AD IV Bolus - Metab
Adinazolam IV Bolus
102
10 2
101
Concentration (ng/mL)
Concentration (ng/mL)
10 1
10 0
0
Time (hours)
100
0
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10
15
20
25
Time (hours)
14-30
K = 0.333hr
k r = 0.133hr
k m = 0.2hr
k mu = 0.2hr
Cp 0 = 55.6ng mL
23
Cp m vsT = 0.2
1
24
0.333
25
6.
Vd = 90L
Vd m = 50L
AUC = 167ng mL hr
AUMC = 500ng mL hr
10
MRT = 3.0hr
11
AUC m = 2.0mg
12
X = 0
13
X u = 2.0mg
14
Xm = 0
15
Xmu = 3.0mg
16
T1 2 = 2hr
17
Cl = 30L hr
18
dR
------- = 7.42 %hr
dT
19
dR = 37.5
----------------%
d ( ln C )
20
d----------------( ln C ) = 0.2hr 1
dt
21
0.333
Slope of
dX u
---------vsT( mid ) = 0.333
dt
22
km X0
X m = --------------------------------------( s + K ) ( s + k mu )
Slope of Cp vs T([AD] vs t) = -
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14.6.1
LABETALOL DATA
Labetalol is a selective - blocking and nonselective -blocking agent used in the treatment of hypertension. It is
excreted unchanged into the urine and extensively metabolized. The metabolites are excreted into the urine and bile.
Labetalol reduces diastolic blood presure.
PROBLEM TABLE 11 - 1. P-col
Time
(hr)
Decrease in BP
(mm Hg)
Cp
(ng/mL)
22.2
14.5
100
20.3
16.5
160
18.5
19.5
275
16.6
22.5
525
PROBLEM TABLE 11 - 1.
Data from a 200 mg IV Bolus dose (Intercept of extrapolated Metabolite data = 22.7 mg/hr)
Plasma Data
Urine Data
Time
(mid)
Labetalol
Excretion rate
Metabolite
Excretion Rate
Time
(hrs)
Cp
(mg/hr)
(mg/hr)
0.5
364
0.5
1.82
5.1
331
1.66
8.2
274
1.5
187
128
2.5
88
9.8
1.37
10.6
10.7
10.5
0.94
9.5
0.64
7.0
4.9
12
2.3
18
0.74
24
0.24
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14.6.2
LABETALOL QUESTIONS
From the above information find the pharmacokinetic parameters:
1) K (elimination rate constant of labetalol) (hr-1 )
2) K2 (elimination rate constant of labetalol metabolites (hr-1 )
3) kr (urinary excretion rate constant of
labetalol)(hr-1 )
4) km (metabolism rate constant of labetalol)(hr-1 )
5) kmu (urinary excretion rate constant of
Metabolites of labetalol)(hr-1 )
6) kmb (biliary excretion rate constant of
Metabolites of labetalol)(hr-1 )
7) Cp0 (IV bolus labetalol) (ng/mL)
8) Vd (labetalol)(L.)
31) Fraction
unchanged.
of
labetalol
excreted
16) Xuinf
17) Xminf
20) T1/2
(labetalol)(hr)
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14.6.3
LABETALOL SOLUTIONS
ku
Xu
kmu
Xmu
km
Xmf
kmf
Xm
Labatalol
24
22
20
Response (mmHg)
Response (mmHg)
Labatalol
23
22
21
20
19
18
17
16
8
Time (hr)
18
16
14
10 2
103
Concentration (ng.mL)
Labatalol Metabolite
Labatalol
Labatalol
102
103
10 1
101
10 0
102
Time (hours)
10-1
0
10
15
20
Time (hours)
25
101
Concentration (ng/mL)
100
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10 -1
0
Tmid (hours)
14-34
K1 = 0.190hr
2.
K2 = 0.792hr
k r = 0.01hr
k mu = 0.38hr
k mb = 0.41hr
Cp 0 = 400ng mL
24
1
d ( ln C )
----------------- = 0.190hr
dt
25
Slope of Cp vs T = 0.190hr
26
Slope of
dX u
--------- vsT( mid ) vs ( t ) = 0.190
dt
27
Slope of terminal portion
of Cp m vsT = 0.190
28
Vd = 500L
AUC = 2105ng mL hr
dR
----------------- = 4.90 %
d ( ln C )
23
k m = 0.18hr
Cp m vsT = 0.79
km X 0
X m = ----------------------------------------( s + K1 ) ( s + K2 )
29
10
AUMC = 11072ng mL hr
11
MRT = 5.26hr
12
AUC = 10.5mg
13
AUC = 91.2mg
14
AUC = 98.3mg
15
X = 0
16
X u = 10.5mg
17
Xm = 0
18
Xmu = 91.2mg
19
Xmb = 98.3mg
20
T1 2 = 3.64hr
21
Cl = 95L
22
dR
------- = 0.93 %hr
dT
30
X mu ( k mu k m X 0 ) K2t K1T
= ---------------------------------- ( e
)
--------e
dt
( K1 K2 )
31
10.5
200
91.2
---------- 100 = 45.6 %
200
33
Fraction of labetalol eliminated as
metabolites in bile:
98.3
---------- 100 = 49.15 %
200
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ZIDOVUDINE DATA
Zidovudine (ZDV - formerly azidithymidine (AZT)) is used to treat HIV positive patients with AIDS and AIDS related
complex (ARC). The in vitro virustatic concentration is 250 mic/mL. While the pharmacokinetics of ZDV is complex,
we can approximate it with the following model. ZDV is excreted unchanged into the urine to UZDV. It is metabolized by hepatic glucuronidation to an inactive metabolite, GZDV, and also metabolized by intracellular phosphorylation to the active metabolite, ZDV-TP. Both metabolites are excreted into the urine (UGZDV and UZDV-TP). The
anti-retroviral activity was shown in the following data:
PROBLEM TABLE 11 - 1. ZDV-TP
Activity
%
Time
(min)
Activity
%
100
80
100
90
76.8
30
100
75
68.5
60
100
50
52.3
120
92
25
24.5
240
82
360
72
480
62
Plasma Data
Time
(hours)
Cp ZDV
(ng/mL)
Urine Data
Cpm GZDV
(ng/mL)
Interval
(hrs)
UZDV Collected
(mg)
0.25
40
0-1
9.2
0.5
75
1-2
4.8
100
2-3
2.5
125
4-6
0.75
1
315
1.5
Rate of
excretion data
AUC
UGZDV (mg)
60
150
170
160
91
160
48
145
13
100
65
10
40
12
25
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= Dose of ZDV
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14.7.2
ZIDOVUDINE QUESTIONS
1) Using Laplace transforms, find the
equation for the rate of excretion of GZDV
into the urine. (For this question use the
following answer set:
a=
I only
b=
III only
c = I + II only
d = II + III only
18) What is the intercept of the extrapolated line from plasma GZDV vs time data
(ng/mL)?
e = All three
(kmu2*km2*D/(K-kmu2))*(exp(-K*t))
II (kmu2*km2*D/(K-kmu2))*(exp(kmu2*t))
19) What is the intercept of the extrapolated line from dUGZDV/dt vs time data
(mg/hr)?
III -(kmu2*km2*D/(K-kmu2))*(exp(K*t))
3) What is d%R/d(lnC)(%)?
5) What is K (hr^-1)?
6) What is kr (hr^-1)?
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14.7.3
ZIDOVULDINE SOLUTIONS
Xm1
km1
ku
Xu
kmu2
Xmu2
km2
kmu1
Xmu1
Xm2
Zidovudine
Zidovudine
110
100
90
Response (% Activity)
Response (% Activity)
80
70
60
0
100
200
300
400
500
Time (min)
Zidovudine
10 1
102
Concentration (ng/mL)
Zidovudine Metobolite
103
102
102
102
101
101
101
100
0
10 12
Time (hours)
UZVD (mg)
Time (hours)
Concentration (ng/mL)
103
0 1 2 3 4 5 6
Concentration (ng/mL)
90
80
70
60
50
40
30
20
10-1
0
Tmid (hours)
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1.
1289.2
40%
-0.08333%hr
1
K = 0.630hr
k r = 0.125hr
k m1 = 0.25hr
457.5ng mL hr
27
952ng mL hr
28
29
30
31
20mg
32
60mg
33
20mg
k m2 = 0.25hr
k mu1 = 0.125hr
10
k mu2 = 0.378hr
11
0.630hr
12
0.250hr
13
14
0.25hr
15
0.630hr
1
1
1
1
16
600ng mL
17
12.6mg hr
18
500ng mL
19
12.6mg hr
20
600ng mL
21
166.7L
22
200L
23
26
105L hr
24
1.1hr
25
1.6hr
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14.8.1
FOSINOPRIL DATA
Fosinopril Sodium is a phosphinic prodrug of the angiotensin converting enzyme (ACE) inhibitor fosinoprilat effective
in the treatment of hypertension and chronic heart failure (CHF). The parent compound is weakly active, if at all. Its
sole metabolite, fosinoprilat, exhibits almost all of the pharmacological activity. After administration, fosinopril is
entirely converted to the active fosinoprolat by esterases in the liver. Unlike other ACE inhibitors, elimination of fosinoprilat is divided equally between renal and hepatic pathways (liver metabolism). The following information was
obtained from a 70 Kg male.
Wherever necessary, please use the following symbols:
Cp = plasma concentration of parent drug, fosinopril
Cpm1 = plasma concentration of metabolite, fosinoprilat.
Cpm2= plasma concentration of metabolite of fosinoplilat.
X = amount of parent compound, fosinopril, in the body
Xm1 = amount of metabolite, fosinoprilat, in the body
Xm2 = amount of metabolite of fosinoprilat in the body
Xu = cumulative amount of parent drug in urine.
Xmu1 = cumulative amount of metabolite, fosinoprilat, in urine.
Xmu2 = cumulative amount of metabolite of fosinoprilat in urine.
ku = renal excretion rate constant of parent drug in plasma.
kmu1 = renal excretion rate constant for metabolite, fosinopril, in plasma.
kmu2 = renal excretion rate constant for metabolite of fosinopril in plasma.
kf = fecal excretion rate constant of parent drug in plasma.
kmf1 = fecal excretion rate constant for metabolite, fosinopril, in plasma.
kmf2 = fecal excretion rate constant for metabolite of fosinopril in plasma.
km1 = metabolism rate constant of fosinopril in plasma.
km2 = metabolism rate constant of fosinoprilat in plasma.
K1 = elimination rate constant of parent drug in plasma = summation of all processes which remove fosinopril.
K2 = elimination rate constant of metabolite1 in plasma = summation of all processes which remove fosinoprilat.
K3 = elimination rate constant of metabolite2 in plasma = summation of all processes which remove the metabolite of fosinoprilat.
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Time
(hr)
Fall in SSBP
(mm Hg)
Fall in SSBP
(mg Hg)
Dose
(mg)
22
10
21
11
20
19
16
40
11
17
22
80
13
16
PROBLEM TABLE 11 - 1.
Plasma Data
(from7.5 mg Fosinoprilat IV Bolus)
Urine Data
(from 20 mg Fosinopril IV bolus)
(Intercept 0.855 mg/hr)
Tme
(hours)
Cp
(Fosinoprilat)
(ng/mL)
Interval
(hr)
Amount (Fosinoprilat)
(mg)
387
0-1
0.158
360
1-2
0.362
335
2-3
0.467
311
3-4
0.513
269
4-6
1.05
6 - 10
1.84
10 - 14
1.42
14 - 22
1.84
22 - 26
0.592
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14.8.2
FOSINOPRIL QUESTIONS
From the parent compound, Fosinopril,
given by IV bolus, find the equation for:
1) X, the mass of parent drug, Fosinopril,
in the body
) Xu, the mass of parent drug, Fosinopril,
in urine.
21) AUMC(fosinoprilat)
20) AUC(fosinoprilat)
22) MRT(fosinoprilat)
24) T 1 2
30) MRT(fosinoprilat)
11) dR/dT
12) dR/d(ln(Cpm1))
32) T ?
13) d(ln(Cpm1))/dT
14) ku, the renal excretion rate constant of parent drug,
Fosinopril, in plasma.
16) kmu1, the renal excretion rate constant for metabolite, Fosinoprilat, in plasma.
17) km2, the metabolism rate constant for the metabolite of Fosinoprilat in plasma.
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Pool
Minus
Small
Med.
Large
Equations
More equations
-0.037
1.35
155
None
-0.050
0.037
5.0
232
X0e-K1t
-0.074
0.06
7.4
420
(X0/Vd)e-K1t
-0.082
0.074
8.2
840
ku X0e -K1t
((kmu1km1 X0)/(K1-K2))(e-K2t-e-K1t )
-0.10
0.135
9.4
940
kf X0e-K1t
((kmu1km1 X0)/(K1-K2))(e-K1t-e-K2t )
-0.135
0.5
10
5676
(k u/K1) X0(1-e-K1t)
((kmu1 X0)/(K1-K2))(e-K2t-e-K1t )
-0.37
0.6
12
13500
(k f/K1) X0(1-e-K1t)
-0.50
0.74
13.5
15700
((km1 X0)/(K1-K2))(e-K2t-e-K1t)
-0.6
0.82
15.5
18000
((km1 X0)/(K1-K2))(e-K1t-e-K2t)
-0.74
0.94
18
76700
((kmu1 X0)/(K1-K2))(e-K2t-e-K1t)
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14.8.3
FOSINOPRIL SOLUTIONS
ku=0
K1= km1
K2= kmu1+km2
km1
K3= kmu2
kmu1
Xm1
Xmu1
km2
kmu2
Xm2
Xmu2
Response
R vs Ln(c)
25
20
Response
15
10
R vs T
23
22
21
20
19
18
17
16
0
10
10
15
0
Concentration
10
12
14
Time (hr)
Fosinoprilat in Urine
Fosinoprilat
Concentration ng/mL
10
10
-1
10
102
0
Time (hr)
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10 15
Time (hr)
20
25
14-46
B - X0e-K1t
H = (km1X0)/(K1-K2)(e-K2t-e-K1t)
X )
K2t
K1t
mu1 m1 0
-{e
e
}
D = -------------------------------
X
C = -----0- e K1t
Vd
K2t
K1t
m1 0
-{e
e
}
A = -------------------------------
( K1 K2 )
( K1 K2 )V d
I = -0.6 mm Hg/hr
12) dR/d(ln(Cpm1))
D = 8.2 mm Hg
13) d(ln(Cpm1))/dT
C = -0.074 hr-1
14) ku, the renal excretion rate constant of parent drug, Fosinopril, in plasma.
15) km1, the metabolism rate constant of parent drug, Fosinopril, in plasma.
F = 0.5 hr -1
16) kmu1, the renal excretion rate constant for metabolite, Fosinoprilat, in plasma.
B = 0.037 hr -1
B = 0.037 hr -1
Fosinoprilat in plasma.
18) K1, the elimination rate constant of parent drug in plasma , the summation of all processes
19) K2, the
F = 0.5 hr -1
elimination rate constant of metabolite in plasma , the summation of all processes which remove Fosinoprilat. D
= 0.074 hr -1
F = 5676 ng/mL
21) AUMC(fosinoprilat)
J = 76700 mg/mL*hr2
22) MRT(fosinoprilat)
H = 13.5 hr
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D = 0.074 hr -1
24) T 1 2
E = 9.4 hr
C = 420 ng/mL
J = 18 L
B = 232 ng/mL
F = 10 mg
29) AUMC(fosinoprilat)
A = 155 mg*hr
30) MRT(fosinoprilat)
I = 15.5 hr
D = 0.074 hr -1
32) T ?
E = 9.4 hr
F = 0.5 hr -1
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14.9 Omeprazole
14.9.1
OMEPRAZOLE DATA
Omeprazole (mw: 345.42) is a gastric proton-pump inhibitor which decreases gastric acid secretion. It is effective in
the treatment of ulcers and esophageal reflux. In normal patients, 20% of the omeprazole is excreted into the feces and
80% of the omeprazole dose is excreted as an inactive metabolite into the urine. In the study by Anderson, et. al., eight
patients were given 20 mg, IV bolus doses of omeprazole. The patients had a mean body weight of 70 kg. Blood and
urine were collected at various intervals throughout the study and the following data was obtained:
TABLE 14-2 Pharmacological
Response
% Acid Secretion
Inhibition
Time (min)
% Acid Secretion
Inhibition
Concentration
(ng/mL)
100
120
74
100
240
62
.6
75
330
56
.5
63
360
47
.35
56
375
27
.15
50
390
25
450
10
570
600
720
Parent Compound
Time (hr)
Cp (ng/mL)
Urine Collection
Interval (hr)
Metabolite
collected (mg)
0.5
336
0-1
1.19
205
1-2
2.07
75
2-3
2.10
28
3-5
3.44
10
5-7
2.38
7-9
1.62
9 - 11
1.08
11 - 13
0.72
13 - 15
0.48
16 - 20
0.44
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14.9.2
OMEPRAZOLE QUESTIONS
Using LaPlace transforms, from Omeprazole, given by IV bolus, find the equation
for:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
13.
14.
15.
16.
17.
) K1 = elimination rate constant of Omeprazole in the body; the summation of all of the ways that it
is removed from the body. (hr-1 )
18.
19.
20.
21.
22.
25.
) AUCiv = Area under the plasma concentration of Omeprazole vs time curve of the IV
dose (mic/L*hr)
28.
) AUMCiv = Area under the first moment of the plasma concentration of Omeprazole vs
time curve of IV dose (mic/L*hr2 )
29.
30.
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31.
32.
33.
34.
) AUCmet = Area Under the Curve of the metabolite excretion rate vs time profile (mg)
35.
36.
37.
38.
39.
40.
Minus
Small Med
Large
-0.8
100
-1
0.1
147
-2
0.2
210
-4
0.3
223
-8
0.4
10
372
-10
0.5
16
444
Answer Pool
Equations
None
X0 e
km X0
K 2 t
K1 t
--------------------------------- (e
e
)
( K 1 K 2 )V dm
K1 t
km X0
K 1 t
K2 t
--------------------------------- (e
e
)
( K 1 K 2 )V dm
k mu X 0
K 2 t
K1 t
--------------------------------- (e
e
)
( K 1 K 2 )V dm
X 0 K 1 t
------ e
Vd
K 1 t
k mu k m X 0 K 2 t
K1 t
----------------------(e
e
)
( K1 K 2 )
K1 t
k mu k m X 0 K 1 t
K2 t
----------------------(e
e
)
( K1 K 2 )
ku X0 e
kf X0 e
ku
K1 t
-----X (1 e
)
K 0
1
-16
0.6
20
556
More Equations
k mu X 0
K 2 t
K1 t
----------------------(e
e
)
( K1 K 2 )
kf
K1 t
-----)
K X0 ( 1 e
k mf k m X 0 1 e K2 t 1 e K 1 t
---------------------- --------------------- ---------------------
( K1 K 2 ) K 2 K 1
-20
0.7
25
643
k m X0
K 2 t
K1 t
----------------------(e
e
)
( K1 K 2 )
k mf k m X 0 1 e K1 t 1 e K 2 t
---------------------- --------------------- ---------------------
( K1 K 2 ) K 1 K 2
-25
0.8
36
756
k m X0
K 1 t
K2 t
----------------------(e
e
)
( K1 K 2 )
k mu k m X 0 1 e K2 t 1 e K 1 t
---------------------- --------------------- ---------------------
( K1 K 2 ) K 2 K 1
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Minus
Small Med
Large
-36
0.9
893
44
Equations
k mu X 0
K2 t
K1 t
----------------------(e
e
)
( K1 K 2 )
More Equations
k mu k m X 0 1 e K1 t 1 e K 2 t
---------------------- --------------------- ---------------------
( K1 K 2 ) K 1 K 2
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14.9.3
OMEPRAZOLE SOLUTIONS
kf
Xf
X
km
Xm
kmu
80
80
70
70
60
-1
60
Response
Response
Xmu
50
40
50
40
30
30
20
20
320
340
360
380
400
420
440
460
Concentration
10
Time (min)
10
10
Concentration
Concentration
10
10
10
10
0
10
10
12
Time (hr)
10
15
20
Time (hr)
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K1 t
1. (B) X = X0 e
2. (A) X u = 0 See model.
3. (A)
dX u
--------- = 0
dt
4. (G)
k
K 1 t
Xf = ------f X 0 ( 1 e
)
K
1
5. (H)
km X0
K 2 t
K1 t
X m = ----------------------(e
e
)
( K1 K 2 )
See model.
k mu k m X 0 1 e K2 t 1 e K1 t
X mu = ---------------------- --------------------- ---------------------
( K 1 K2 ) K2 K1
6. (I)
7. (D)
k mu k m X 0 K2 t K 1 t
dX mu
------------- = ----------------------(e
e
)
dt
( K 1 K2 )
8. (A)
X mf = 0
9. (C)
X
K 1 t
C p = ------0- e
Vd
10.(A)
km X 0
K2 t
K 1 t
C pm = ---------------------------------(e
e
)
( K 1 K 2 )V dm
11.(I)
See model.
dR 0.4% 25%
------- ------------------ -------------dt minute
hr
response ONLY!
12.(H)
dR
74%-57%
17%
--------------- = ---------------------------------------------- = ------------- 25%
d ln C p
ng
ng
0.693
ln 1.0 ------ ln 0.5 -----ml
ml
13.(B)
d ln C p
1
dR d ln C
25%
1
--------------- = ------- ---------------p = -------------- ----------- = 1 hr
dt
dt
dR
hr
25%
14.(A)
kr = 0
15.(C)
1
Xf K 1
1
4mg 1hr
- = ----------------------------- = 0.2hr
k f = ------------X0
20mg
See model.
0.2hr-1
16.(I) k m =
K 1 k f = 1hr
0.2hr
Also,
= 0.8hr
kf
is 20% of
if you have
K1 ,
or 20% of 1hr-1 =
k f .or
1
X mu K 1
1hr = 0.8hr 1
k m = ---------------= 16mg
-------------------------------X0
20mg
. Also,
km
is 80% of
K1 ,
or 80% of 1hr-1 =
0.8hr-1
17.(A)
d ln C
1
K 1 = ------------------p = 1hr
dt
18.(H)
t 1 2 = 0.693
------------- = 0.693 0.7hr
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20
X f ( inf ) = --------- 20mg = 4mg
100
22.(C)
23.(I)
Dose- ----------------20mg 20
, 000g- 36L
V d = ----------------------------------C p0
ng
g
556 -------556 -----mL
L
24.(G)
ng- 556 g
-----C p0 556 ------mL
L
25.(G)
AUC IV =
From graph.
C p ( last )
p ( n ) + C p ( n + 1 )
C
--------------------------------------t + -----------------
K1
2
or
C p0
AUC IV = -------K1
556 + 336
336 + 205
205 + 75
75 + 28
AUC IV = ------------------------ 0.5 + ------------------------ 0.5 + --------------------- 1 + ------------------ 1 +
2
2
2
2
or
10
g hr
+ 10
28
------------------ 1 + ------ = 578.75 556 ---------------- 2
1
L
ng
556 ------- hr
mL = 556
AUC IV = ----------------------------L
1hr
26.(D)
2
L
27.(E)
10 g hr
------ ----------------1
L
28.(G)
AUMC IV =
tn Cp (n ) + tn + 1 Cp (n + 1 )
C p ( last ) tlast C p ( last )
------------------------------------------------------- t + -----------------+ ---------------------------
2
2
K1
( K1 )
2
2
2
2
g hr
( 75 ) + 3 ( 28 )
3 ( 28 ) + 4 ( 10 )
10 4 ( 10 )
2--------------------------------- 1 + ---------------------------------- 1 + ------ + -------------- = 541.75 556 ------------------
2
1
L
2
2
1
2
hr
556 g
------------------AUMC
L
= ------------------ ----------------------------- 1hr
hrAUC
556 g
---------------L
29.(A)
MRT IV
30.(A)
31.(A)
32.(A)
33.(A)
Xm 0 = 0
34.(F)
AUC met =
or
1 = ------------1 - = 1hr
MRT IV = -----1
K1
1hr
See model.
X m ( inf ) = 0 See model.
V dm =
Can not determine from information given. Need
C pm0 = 0 See model.
Xmu
80
= --------- 20mg = 16mg .
100
C pm
information.
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14-55
39.(C) k mu = K 2 = 0.2hr 1 = is
which is K1 .
40.(A) K m f = 0 See model.
k small
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k l arg e 1hr
14-56
M1 administration (mg/kg)
(MAP) decrease
I.V. bolus
(MAP) decrease
25
0.01
60
36.5
0.03
57.4
48.5
0.1
54.7
59
0.3
49.3
44.5
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Time (hr)
14-57
The parent compound EXP3312 and metabolite M1 levels were measured in the
plasma over time. The data obtained from the active M1 metabolite and the inactive partent drug EXP3312 are shown below. The standard dose for each rat was
0.3mg/kg.
TABLE 14-6
time (hr)
EXP3312
M1
Cp (mic/mL)
Cp (mic/mL)
0.15
0.32
0.3
0.59
0.5
0.4
0.26
1.34
0.11
1.61
0.045
1.26
0.81
10
0.3
12
0.18
I = 3.81 mic/mL
Use the following data was obtained when an intravenous infusion of a different
dose was given to an average rat over 45 minutes.
TABLE 14-7
time (hr)
Plasma concentration
(mic/mL)
0.25
0.139
0.5
0.26
0.75
0.35
0.29
0.12
0.05
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14-58
2.
3.
4.
5.
The slope of terminal portion of dXmu/dt vs: t (mid) on semi-log paper (hr-1)
6.
The slope of stripped portion of Cpm vs: t or (Concentration of M1 vs: t) on semi-log paper
(hr-1)
7.
8.
9.
10.
11.
12.
13.
14.
Vd of EXP3312 (L)
15.
Vdm of M1 (L)
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
(mic/mL*hr))
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14-59
31.
32.
33.
34.
Clearance (L/hr/kg)
35.
36.
37.
Find the plasma concentration if the infusion in Table 14-7 on page 58 was discontinued at 5
hours instead of 45 minutes. (mic/mL)
38.
Find the time need for the concentration to drop to 0.23 mic/mL after the infusion in question 37
is discontinued (hours).
39.
Determine the new infusion rate necessary to maintain a plasma concentration of Cpss 1.0 mic/
mL of the average rat. (mg/hr)
40.
Find a loading dose for the average rat which would give the Cpss of 1.0 mic/mL immediately
(mg)
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14-60
Pool
Minus
ones
Small
ones
Big
ones
Bigger
ones
-0.121
0.55
1.05
-0.26
0.019
0.62
1.15
-0.391
0.039
0.72
1.32
-0.567
0.063
0.80
1.69
-0.621
0.105
0.83
2.63
-0.866
0.146
0.866
3.5
Equations
None
X0 e
K 1 t
X0 K1 t
------ e
Vd
-1.112
0.169
0.94
4.17
km X0
K1 t
K 2 t
---------------------------------(e
e
)
( K 1 K 2 )Vd m
k mu X 0
K2 t
K 1 t
--------------------------------- (e
e
)
( K 1 K 2 )V dm
k mu k m X 0 K 2 t K1 t
----------------------(e
e
)
( K 1 K2 )
K1 t
k mu k m X 0 K 1 t K2 t
----------------------(e
e
)
( K 1 K2 )
ku
K1 t
-----X (1 e
)
K 0
1
km X0
K2 t
K 1 t
---------------------------------(e
e
)
( K 1 K 2 )Vd m
K 1 t
kuX 0 e
kf X0 e
Equations
k mu X 0
K2 t
K1 t
----------------------(e
e
)
( K 1 K2 )
kf
K1 t
-----X (1 e
)
K 0
k mf k m X 0 1 e K 2 t 1 e K 1 t
---------------------- --------------------- ---------------------
( K1 K 2 ) K 2 K1
-1.981
0.26
0.95
4.83
km X0
K2 t
K 1 t
----------------------(e
e
)
( K1 K 2 )
k mf k m X 0 1 e K 1 t 1 e K 2 t
---------------------- --------------------- ---------------------
( K1 K 2 ) K 1 K2
-2.63
0.42
0.96
7.2
km X0
K1 t
K 2 t
----------------------(e
e
)
( K1 K 2 )
k mu k m X 0 1 e K 2 t 1 e K 1 t
---------------------- --------------------- ---------------------
( K1 K 2 ) K 2 K1
-3.71
0.48
0.99
10.1
k mu X 0
K2 t
K 1 t
----------------------(e
e
)
( K1 K2 )
k mu k m X 0 1 e K 1 t 1 e K 2 t
---------------------- --------------------- ---------------------
( K1 K 2 ) K 1 K2
This exam is given early at the request of those students who had conflict with the time agreed upon. They signed a
document stating that they would not share their experience with anyone under pain of prosecution for adademic misconduct which will result minimally in an F for the course. You also must sign this document.
I ___________________________________________ did not comunicate in anyway anything at all regarding this
exam nor give or receive any assistance during the exam upon my honor as a health professional and under pain of
prosecution for adademic misconduct.
Signed__________________________________________________________Date__________________
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CHAPTER 15
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15-1
Echizen and Eichelbaum (Clin Pkin 1986; 11:425-49) and Kleinbloesem et al (Clin Pcol Therap 1986; 40: 21-8)
reviewed the pharmacokinetics of Nifedipine. While the drug is not routinely given by IV bolus and does not strictly
conform to a one compartment model, let's treat the data as if those problems can be ignored. The following data is
offered for evaluation:
TABLE 1-1. Nifedipine
Time (hr)
Cp
(mcg/L)
Cm1 (mcg/L)
0.5
24.7
44.4
71.8
IV Bolus Profile
Xm1f (mg)
Xm1u (mg)
.14
.59
Xm2f (mg)
Xm2u (mg)
139
65.6
96.5
.44
1.83
.028
.11
31.1
100
.77
3.25
.073
.29
14.6
94.7
1.1
4.65
.135
.54
12
76.5
1.69
7.10
.291
1.15
24
34
2.77
11.63
.75
2.95
3.6
15.1
1.3
5.0
7 days
Oral information
Brand
Generic
Route
IV
Oral Capsule
Oral Capsule
Dose (mg)
25
10
10
AUC (ug/L*hr)
785
236
204
AUMC (ug/L*hr2 )
2093
866
816
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15.1.1
NIFEDIPINE QUESTIONS:
Find:
1) MRT iv (hr)
23) Ka, the apparent absorbtion rate constant, for the generic capsule (hr-1 )
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15-3
Small
Answer Pool
Medium
Large
Dosing changes:
a) 0.00
a) 1.85
a) 59
a) 10 mg once daily
b) 0.05
b) 2.67
b) 85
b) 10 mg BID
c) 0.33
c) 3.67
c) 92.5
c) 10 mg TID
d) 0.375
d) 4.0
d) 101
d) 10 mg QID
e) 0.65
e) 4.32
e) 124
e) 20 mg once daily
f) 0.75
f) 9.3
f) 147
f) 20 mg BID
g) 0.85
g) 18.5
g) 185
h) 1.0
h) 32
h) 202
h) 20 mg QID
i) 1.33
i) 38
i) 248
i) 30 mg once daily
j) 1.57
j) 49
j) 294
j) 30 mg BID
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15.1.2
NIFEDIPINE SOLUTIONS
1.
21.
MRT iv = 2.67hr
k e = 0.375hr
3.
T1 2 = 1.85hr
4.
Cp 0 = 294ug L
5.
Vd = 85L
generic
capsule
generic
capsule
generic
capsule
MRT = 4hr
2.
Oral
22.
Oral
MAT = 1.33hr
23.
Oral
Ka = 0.75hr
24.
6.
1.85hr
7.
Cp 1 = 202ug L
25.
8.
AUC 0 1 = 248ug L hr
9.
Cl s = 32L hr
10.
Cl r = 0
11.
Cl h = 32L hr
12.
Er = 0
27.
N = 4.32
13.
Eh = 0.33
28.
Cp
14.
Absolute bioavailability for brand
name capsule = 0.75
29.
Cp
15.
30.
Cp
31.
No change
32.
No change
33.
No change
34.
No change
Oral
generic
capsule
Cp max = 38ug L
26.
Comparative bioavailability of the
oral capsules B/A:
AUC = 0.86 (ok)
Oral
brand
name
capsule
MRT = 3.67hr
16.
Oral
brand
name
capsule
brand
name
capsule
MAT = 1.0hr
17.
Oral
Ka = 1.0hr
18.
Oral
ss
ss
ss
max =
185ug L
ave =
59ug L
min =
9.3ug L
brand
name
peak
time
1.57hr
19.
Oral
brand
name
Cp max = 49ug L
20.
Absolute
generic = 0.65
bioavailability
for
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15-5
TABLE 1-4
IV bolus
Dose (mg)
AUC (mg/L*hr)
2
AUMC(mg/L*hr )
Generic
250
250
594
273
253
9428.6
4605.5
4184.6
2.95
Tpeak (hr)
Cpmax
Bioavailability (f)
Brand
500
14.35
1.0
.92
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15-6
15.2.1
VALPROATE QUESTIONS
of Valproate (hr).
b) 15.87 c) 16.54
d) 16.87 e) 17.08
b) 0.063
c) 0.060
d) 0.0593
e) 0.0585
b) 11 c) 11.5
d) 11.7 e) 11.8
b) 0.063
c) 0.84
d) 1.25
d) 2.5
b) 0.0084
c) 0.063
d) 0.084
e) 0.84
b) 1.65
c) 2.12
d) 2.32
e) 2.5
7) What is the maximum acceptable dosing interval for normal patients (hr)?
a) 8
b) 12
c) 18
d) 24
e) 25.5
b) 0.727
c) 0.842
d) 1.25 e) 1.42
9) If you dosed this patient 500 mg BID with the brand name product, what would be your maximum concentration at
steady state (mg/L)?
a) 87.3
b) 70.9
c) 65.2
d) 52.8
e) 45.8
b) 32.7
c) 30.1 d) 27.1
e) 22.9
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b) 49.8
c) 47.7
d) 45.8
e) 34.4
12) What loading dose would you give to get to Cpss right away (mg)?
a) 250
b) 500
c) 750
d) 1000
e) 1500
13) If you changed the dosage regimen to 250 mg QID, what would happen to the Cpssmax, Cpssave, Cpssmin?
a) Cpssmax - up, Cpssave - up, Cpssmin - up
b) Cpssmax - down, Cpssave - down, Cpssmin - down
c) Cpssmax - same, Cpssave - same, Cpssmin - same
d) Cpssmax - up, Cpssave - same, Cpssmin - down
e) Cpssmax - down, Cpssave - same, Cpssmin - up
b) 0.75
c) 0.85
d) 0.93e) 1.0
b) 0.75
c) 0.85
b) 15.87 c) 16.54
d) 0.93e) 1.0
d) 16.87 e) 17.08
b) 0.75
c) 0.85
d) 0.93e) 1.0
b) 1.33
c) 1.18
d) 1.08
e) 1.0
b) 2.45
c) 2.59
d) 2.76
e) 2.95
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15-8
a) 8.1
b) 9.3
c) 10.7
d) 12.6
e) 14.4
In patients who are also currently on phenobarbital their intrinsic clearance of valproate increases by 50% as the phenobarbital induces the enzymes which metabolize valproate. Further questions refer to this condition.
b) 0.063
c) 0.84
d) 1.25
d) 2.5
d) 0.059
e) 0.042
b) 0.084
c) 0.063
b) 12
c) 17
d) 18
e) 24
25) What dosage regimen would you recommend to try to maintain his plasma concentrations within 110% of the maximum and 90% of the minimum concentrations attained when he was normal?
a) 750 mg BID
b) 500 mg TID
c) 750 mg TID
d) 250 mg QID
e) 500 mg QID
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15-9
15.2.2
VALPROATE SOLUTIONS
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15-10
IV
Brand
Name
Generic
Dose (mg)
10
20
20
AUC (ug/ml*hr)
0.20
0.04
0.035
AUMC (ug/ml*hr2
0.32
0.14
0.1225
Answer Pool
Itty- Bitty
Tiny
Puny
Small
Medium
Large
0.016
0.1
1.1
10
100
yes
0.00016
0.0251
0.125
1.6
20
125
0.0005
0.035
0.25
1.75
30
225
0.00074
0.042
0.35
1.9
40
375
0.00084
0.05
0.42
2.6
50
435
0.0016
0.067
0.53
3.5
60
550
0.005
0.075
0.625
4.2
70
675
20 mg TID
0.0074
0.0875
0.727
5.0
80
750
20 mg BID
0.0084
0.091
0.875
7.27
90
875
20 mg QD
0.0090
0.096
0.91
8.75
96
995
20 mg QID
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Words
15-11
15.3.1
You want to maintain his plasma concentrations between 110% of Cpssmax and 90% of
Cpssmin . How would you change the dosage
regimen to if your patient suffered from:
(in no case was there a change in Vd)
32) stenosis of the kidney (Fr = 0.67)?
33) renal failure (Fi = 0.34)?
34) stenosis of the liver (Fr = 0.67)?
35) cirrhosis of the liver. (Fi = 0.67)?
36) treatment with phenobarbital (Fi =
1.33)?
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15-12
15.3.2
19.
MRT iv = 1.6hr
2.
k = 0.625hr
3.
Brand
name
Cp max = 0.0084ug mL
20.
Generic - f = 0.0875
T1 2 = 1.1hr
21.
4.
Cp 0 = 0.125ug mL
22.
5.
Vd = 80L
23.
Generic - Ka = 0.53hr
6.
Cp 1 = 0.067ug mL
24.
25.
Generic
7.
AUC 0 1 = 0.096ug mL hr
Cl s = 50L hr
9.
Cl r = 0
10.
Cl h = 50L hr
11.
Cl int = 100L hr
28.
N = 7.27
12.
Er = 0
29.
Cp
13.
Eh = 0.53
30.
Cp
31.
Cp
32.
20 mg TID
33.
20 mg TID
34.
20 mg BID
35.
20 mg TID
36.
20 mg QID
15.
Cp max = 0.0074ug mL
8.
14.
26.
0.875
Comparative
bioavailability
27.
Yes, the tablets are bioequivalent all parameters are within federal guidelines.
16.
17.
18.
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ss
ss
ss
max =
0.0251ug mL
avg =
0.005ug mL
min =
0.00016ug mL
15-13
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15-14
15.4 Verapamil
Verapamil is a calcium channel blocker with vasodilatory and antiarrhythmic effects. It is about 95% metabolized by
the liver with the metabolites showing up in the urine and feces.
Hepatic blood flow in normals is 1.6 L/min
Renal blood flow in normals is 1.2 L/min
TABLE 1-7 Verapamil
Route
Data
IV
Brand
Generic
Oral Tablet
Oral Tablet
Dose (mg)
15
80
80
AUC (ng/mL*hr)
300
480
400
AUMC (ng/mL*hr2 )
1600
2690
2280
TABLE 1-8
Tiny
Small
Medium
Large
Dosing regimens
Bioavailability answers
1.06
26
116
40 mg qd
Yes
0.063
2.15
46
267
40 mf bid
0.188
2.50
47.5
369
40 mg tid
0.250
2.70
50
533
40 mg qid
0.270
3.69
56
637
80 mg qd
0.300
5.33
61.5
830
80 mg bid
0.370
5.60
76.5
905
80 mg tid
0.693
5.70
83
970
80 mg qid
0.85
6.37
90.5
1160
160 mg qd
0.905
8.30
97
2670
160 mg bid
No, more than one of the required ratios are no within limits
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15.4.1
VERAPAMIL QUESTIONS
1) MRT iv (hr)
2) Ke (elimination rate constant) for Verapamil (hr-1 )
3) T 1/2 for Verapamil
4) Cp0 for iv dose (ug/L)
5) Vd for Verapamil (L)
7) Cp of Verapamil at one hour after the IV
dose
8) AUC from 0 to one hour for the IV dose
23) Ka, the apparent absorbtion rate constant, for the generic tablet (hr-1 )
24) Peak time for the generic tablet (hr)
25) Cpmax , the maximum concentration
of the generic oral tablet give as a single
dose (ug/L)
26) Comparative bioavailability of the oral
tablets
27) Are the tablets bioequivalent?
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15-16
15.4.2
VERAPAMIL SOLUTIONS
1.
17.
MRT iv = 5.33hr
Brand
Ka = 3.69hr
2.
k e = 0.188hr
3.
T1 2 = 3.69hr
0.85hr
4.
Cp 0 = 56ug L
19.
5.
Vd = 267L
18.
name
tablet
name
tablet
Cp max = 76.5ug L
6.
20.
Generic - Absolute bioavailability
- f = 0.25
7.
Cp 1 = 47ug L
21.
22.
8.
AUC 0 1 = 50ug L hr
9.
Cl = 50L hr
23.
Generic - Ka = 2.70hr
10.
Cl r = 2.50L hr
24.
11.
Cl h = 47.5L hr
25.
12.
Er = 0.063
26.
13.
Eh = 0.49
Correction - should
Brand
name
tablet
name
tablet
MRT = 5.60hr
16.
Brand
MAT = 0.270hr
27.
The tablets are not bioequivalent peak time ratio is not within limits.
28.
N = 2.15
29.
Cp
ss
max =
116ug L
ss
Cp
ss
min =
26ug L
32.
No change in dosing regimen - 80
mg TID
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33.
40 mg TID
35.
40 mg BID
34.
No change in dosing regimen - 80
mg TID
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15-18
hydrochloride Data
IV
Oral tablet
Brand
Oral tablet
Generic
Dose (mg)
AUC (ng/mL*hr)
83
87
65
AUMC (ng/mL*hr2 )
291
348
292
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15-19
15.5.1
MRTiv.
(291/83=3.5)
2.
K. (1/3.5=0.285
3.
4.
5.
Ku (0.1*0.285=0.029)
6.
Km (0.9*0.285=0.256)
7.
Cls (f*D/AUC=1*2000/83=24L/hr)
8.
Vd (Cls/K=Vd= 24/0.285=84L
9.
10.
11.
12.
27.
29.
Taumax (2.8*2.4=6.74 hr
30.
31.
N (6/2.4 =2.5)
32.
33.
34.
35.
Cpssmin? ( 5 ng/mL)
13.
MRT (348/87=4.0)
14.
15.
Ka (1/0.5 = 2.0)
16.
Tp (ln(ka/K)/(ka-K)=1.95/1.715=1.14hr
17.
18.
20.
21.
22.
Tp (ln(1/0.285)/(1-0.285)=1.26/.715=1.76
hr
23.
24.
26.
36.
FClr0.94
37.
Clr*2.3
38.
FClh1
39.
Clh*21.6
40.
FCls.99
41.
Cls*23.9
42.
K*0.284
43.
t1/2*2.44
44.
Nmax
45.
Taumax6.83
46.
47.
N 2.46
48.
49.
Cpssmax? 30
50.
Cpssavg? 15
51.
Cpssmin? 5.5
2.8
6
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52.
FClr.52
77.
Taumax8
53.
Clr*1.23
78.
54.
FClh2
79.
N6
55.
Clh*21.6
80.
56.
FCls.95
57.
Cls*22.8
81.
Cpssmax? 32
58.
K*0.271
82.
Cpssavg? 17
59.
t1/2*2.55
83.
Cpssmin? 7.5
60.
Nmax
61.
Taumax
62.
63.
N 2.35
64.
84.
FClr1
85.
Clr*2.4
65.
Cpssmax? 31
86.
FClh.56
66.
Cpssavg? 15
87.
Clh*12
67.
Cpssmin? 6.1
88.
FCls.6
89.
Cls*14.4
90.
K*.171
91.
t1/2*4.04
92.
Nmax 2.8
2.8
7.13
68.
FClr1
93.
Taumax11.3
69.
Clr*2.4
94.
70.
FClh.833
95.
N 1.48
71.
Clh*18
96.
72.
FCls.85
73.
Cls*20.4
97.
Cpssmax? 33
74.
K*.243
98.
Cpssavg? 18
75.
t1/2*2.85
99.
Cpssmin?8.4
76.
Nmax 2.8
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24 mL/min/Kg Blood
QR = 19 mL/min/Kg Blood
TABLE 1-10 Fosinopril
Data
IV
Brand Name
Tablet
Generic
Tablet
Dose (mg)
7.5
10
10
AUC (ng/ml*hr)
5700
1500
1400
AUMC (ng/ml*hr2)
78000
25000
23100
Answer Pool:
0.015
0.19
1.3
10
100
yes
0.00016
0.0251
0.0005
0.035
0.21
1.6
13.7
142
0.25
1.75
16.6
192
0.00074
0.042
0.36
1.9
18
253
0.00084
0.05
0.42
2.8
50
387
0.0016
0.067
0.53
3.5
67
402
0.005
0.073
0.65
4.0
73
416
10 mg qid
0.0064
0.0875
0.72
5.6
84
750
10 mg tid
0.0084
0.091
0.84
7.0
93
875
10 mg bid
0.0090
0.096
0.93
9.5
96
995
10 mg qd
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15.6.1
FOSINOPRIL QUESTIONS
1) MRT for fosinoprilat (hr)
2) Ke for fosinoprilat (hr-1)
3) T ?
4) Cp0
Your patient is controlled by 10 mg TID of the brand name oral tablet when he is
healthy. For This patient and this dosage regimen, what is his:
28) N ?
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and 80% of
. How would you change the dosage regimen to if your patient suffered from:
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15.6.2
Oral
brand
name
tablet
1.
MRT = 13.7hr
2.
k = 0.073hr
3.
T1 2 = 9.5hr
4.
Cp 0 = 416ng mL
21.
5.
Vd = 18L
22.
6.
Cp 1 = 387ng mL
7.
AUC 0 1 = 402ng mL
23.
8.
Cl s = 1.3L hr
24.
Cl r = 0.65L hr
25.
Generic
9.
10.
Cl h = 0.65L hr
11.
Cp max = 0.073ng mL
20.
Oral generic tablet absolute bioavailability is 0.19
Er = 0.015
13.
Eh = 0.0064
Oral
is
15.
30.
Cp
31.
Cp
32.
10 mg TID
33.
10 mg BID
34.
10 mg TID
35.
10 mg TID
36.
10 mg QID
name
tablet
MRT = 16.6hr
name
tablet
MAT = 2.8hr
17.
Oral
Ka = 0.36hr
18.
brand
tablet
Cp
brand
27.
Yes! the tablets are bioequivalent
The AUCs, peak times, and Cp max s are
29.
Oral
tablet
26.
Comparative bioavailability of the
oral tablets = 0.93
14.
Oral brand name tablet absolute
bioavailability is 0.21
16.
generic
Cp max = 0.067ng mL
N = 0.84
brand
tablet
MAT = 2.8hr
28.
Oral
generic
MRT = 16.6hr
0.65L hr
12.
Oral
name
tablet
5.6hr
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ss
ss
ss
max =
253ng mL
avg =
192ng mL
min =
142ng mL
15-26
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15.7 Remoxipride
Remoxipride (MW 296 - Unionized Base pKa 9.4) is a new antipsychotic of the benzamide type (See figure 1). The
pharmacokinetics were studied by Movin-Osswald and Hammarlind-Udenaes (Brit. J Clin Pcol 1991 32(3) 355ff).
Their results are summarized in table 1. The HCl salt of the drug was given (MW 332.5) to these patients in this study
but the drug concentration was reported as the free base in the plasma. In this study, 25% of the Remoxipride was
excreted unchanged, 75% was metabolized. The hepatic and renal blood flow in these patients was 1.5 and 1.2 L/min
respectively. REMEMBER TO PAY ATTENTION TO UNITS.
FIGURE 4-5.
Remoxipride
Data
IV bolus
Oral Solution
Tablet A
Tablet B
100
100
Dose (mg)
50
AUMC (umole/
L*hr2 )
145
158.7
319.6
282.6
AUC (umole/L*hr)
20.9
19.8
37.6
31.4
Tp (hr)
3.6
Cpmax (mg/L)
.8
.75
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15.7.1
REMOXIPRIDE QUESTIONS
1) Find the MRT of the IV product (hr).
2) Find the elimination rate constant of remoxipride (hr-1 ).
3) Find the Cp0 of the IV product (mg/L)
4) Find the volume of distribution of the IV product. (L)
5) Find the half life of remoxipride (hr).
6) Find the clearance of remoxipride (L/hr).
7) Find the renal clearance (L/hr).
8) Find the hepatic clearance
9) Find the renal extraction ratio.
10) Find the hepatic extraction ratio.
11) Find the MRT of remoxipride given as the oral solution (hr).
12) Find the MAT of remoxipride given as oral solution (hr).
13) Find the absorption rate constant of remoxipride given as an oral solution (hr-1 ).
14) Find the bioavailability of the oral solution (f).
15) Find the peak time of the oral solution (hr).
16) Find the MRT of remoxipride given as Tablet A, the brand name product.
17) Find the MAT of remoxipride given as Tablet A.
18) Find the apparent absorption rate constant (ka) of remoxipride given as Tablet A.
19) Find the peak time of Tablet A.
20) Find the single dose Cpmax for tablet A (mg/L)
21) Find the mean dissolution time (MDT) of Tablet A, the brand name product (hr).
22) Is Tablet B, the generic product is bioequivalent to Tablet A. Why or why not?
23) Find N for BID dosing.
24) Find Cpss max for two caps bid for the brand name product.
25) Find Cpss avg for two caps bid for the brand name product.
26) Find Cpss min for two caps bid for the brand name product.
27) Which change in physiological status would result in the most significant change in
the TBC of remoxipride?
a) Changes which effect the flow of blood to the liver.
b) Changes which effect the flow of blood to the kidney.
c) Changes which effect the function of the liver.
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15.7.2
REMOXIPRIDE SOLUTIONS
1.
MRT = 6.93hr
2.
k e = 0.144hr
3.
Cp 0 = 0.88mg L
4.
Vd = 50L
5.
T1 2 = 4.8hr
6.
Cl = 7.28L hr
7.
Cl r = 1.8L hr
8.
Cl h = 5.46L hr
9.
Er = 0.025
10.
Eh = 0.06
11.
12.
13.
14.
15.
16.
17.
18.
Tablet A Ka = 0.637hr
19.
20.
21.
Tablet B is not bioequivalent to Tablet A because peak time and Cp max are out of
federal guidelines.
22.
23.
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24.
Cp
25.
Cp
26.
Cp
ss
ss
ss
max =
3.88mg L
avg =
1.85mg L
min =
0.685mg L
27.
The change in physiological status that would result in the most significant change
in TBC of remoxipride
is (C) - changes
which effect the function of the liver.
28.
29.
New Cl h = 9.0L hr
30.
New Cl s = 10.8L hr
31.
New T1 2 = 3.2hr
32.
New N = 3.75
33.
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15.8 Naproxen
Naprosyn@ (naproxen) is a nonsteroidal anti-inflammatory drug (NSAID) with
analgesic properties. It is well absorbed (f = 0.95) and highly protein bound (98%)
with a volume of distribution of about 10 L and a half-life of 13 hours in normal
adults. It is almost entirely cleared by hepatic function (CLr = 1%) with about onethird being metabolized to the 6-o-desmethylnaproxen (which is further metabolized by conjugation) and two-thirds being conjugated directly. Both the 6-o-desmethyl metabolites as well as the conjugates are inactive.
Normal dosing is 500 mg Naproxen BID. You stock 200 and 500 mg tablets in
your HMO.
For the following conditions, new parameters are given in parentheses.
Concomitant treatment with Probenecid, a uricosuric which increases the urinary
excretion of uric acid, while not interfering with the protein binding, effectively
blocks the hepatic conjugation process reducing the hepatic function (Clinth ) to
one-third of normal.
In chronic renal failure (Fir = 0.1) the protein binding is reduced (94%) because of
uremia. This results in a marginal increase in half-life (14 hr.)
In rheumatoid arthritis, hypoalbuminaemia results in a reduction in protein binding
(97%) and increase in the volume of distribution (13 L).
Elderly patients exhibit a decrease in binding (96%), but no change in half-life or
volume of distribution.
For each of the conditions, (with Probenecid, chronic renal failure, arthritic, and
elderly), please recommend a dosage regimen which would give approximately the
same plasma concentrations of free naproxen obtained in the normal case (+ 10%.)
Constants:
L - renal blood perfusion 70kg 60min
L
Q r = 0.0191 --------------------------- 80 -----blood
min kg
hr
hr
L
min
L
Q H = 0.0238 -------------------- hepatic blood perfusion 70kg 60--------- 100 -----blood
min kg
hr
hr
Extraction ratios are calculated for normals and considered to be constant throughout.
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15.8.1
NAPROXEN QUESTIONS
TABLE 1-1. Question
Patient Condition
Normal
Probenecid
Chronic
Rheumatoid
treatment
Renal Failure
arthritis
Elderly
Dose(mg)
27
51
75
99
28
52
76
100
fu
29
53
77
101
Vd (L)
30
54
78
102
k (hr-1)
31
55
79
103
T 1/2 (hr)
32
56
80
104
AUC (mg/L*hr)
33
57
81
105
% Cl h
34
58
82
106
% Cl r
35
59
83
107
Cl tot (L/hr)
10
36
60
84
108
Cl h (L/hr)
11
37
61
85
109
Cl r (L/hr)
12
38
62
86
110
Eh
13
Er
14
Cl h
Cl r
Cp
(L/hr)
15
39
63
87
111
(L/hr)
16
40
64
88
112
FR h
17
41
65
89
113
FI h
18
42
66
90
114
FR r
19
43
67
91
115
FI r
20
44
68
92
116
FCL
21
45
69
93
117
(hr)
22
46
70
94
118
23
47
71
95
119
24
48
72
96
120
int
int
ss
max free
g
------ mL
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Cp
Cp
ss g
-------avg free mL
25
49
73
97
121
g
------ mL
26
50
74
98
122
ss
min free
Answer Pool
S
XL
XXL
XXXL
0.000067
0.0182
0.100
1.0
10.0
100
0.0005
0.0200
0.133
1.1
11.3
200
0.0050
0.0300
0.177
1.4
12.0
303
0.0080
0.0400
0.182
1.5
13.0
356
0.0089
0.0495
0.267
1.6
13.3
500
0.0092
0.0533
0.315
1.7
14.0
595
0.0095
0.0600
0.333
1.8
26.5
891
0.0097
0.0610
0.341
1.9
31.7
1044
0.0098
0.0675
0.528
2.0
38.1
2000
0.0099
0.0700
0.533
2.1
45.0
3000
0.0790
0.577
2.2
50.0
0.0798
0.615
2.9
53.0
0.0857
0.675
3.0
62.0
0.0923
0.700
5.3
80.0
0.0950
0.790
6.2
86.0
0.0970
0.798
8.0
92.0
0.0990
0.857
8.5
97.0
0.0999
0.923
9.0
99.0
0.09997
0.95
9.9
99.97
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15.8.2
NAPROXEN SOLUTIONS
TABLE 1-1. Question
Patient Condition
Normal
Probenecid
treatment
Chronic
Rheumatoid
Renal Failure
Elderly
arthritis
1. 500 mg
27. 200
51. 500
75. 500
99. 200
2. 0.95
28. 0.95
52. 0.95
76. 0.95
100. 0.95
fu
3. 0.02
29. 0.02
53. 0.06
77. 0.03
101. 0.04
Vd (L)
4. 10
30. 10
54. 31.67
78. 13
102. 10
k (hr-1)
5. 0.0533
31. 0.0182
55. 0.0495
79. 0.061
103. 0.533
T 1/2 (hr)
6. 13
32. 38.1
56. 14
80. 11.3
104. 13
AUC (mg/L*hr)
7. 891
33. 1044
57. 303
81. 595
105. 356
% Cl h
8. 99
34. 97
58. 99.97
82. 99
106. 99
% Cl r
9. 1
35. 3
59. 0.03
83. 1
107. 1
Cl tot (L/hr)
10. 0.533
36. 0.182
60. 1.57
84. 0.798
108. 0.533
Cl h (L/hr)
11. 0.528
37. 0.177
61. 1.57
85. 0.790
109. 0.528
Cl r (L/hr)
12. 0.005
38. 0.005
62. 0.005
86. 0.008
110. 0.005
Eh
13. 0.005
Er
14. 0.000067
Dose(mg)
Cl h
Cl r
(L/hr)
15. 26.5
39. 8.84
63. 26.5
87. 26.5
111. 13.26
(L/hr)
16. 0.267
40. 0.267
64. 0.00889
88. 0.267
112. 0.133
FR h
17. 1
41. 1
65. 1
89. 1
113. 1
FI h
18. 1
42. 0.333
66. 3
90. 1.5
114. 1
FR r
19. 1
43. 1
67. 1
91. 1
115. 1
FI r
20. 1
44. 1
68. 0.1
92. 1.5
116. 1
FCL
21. 1
45. 0.341
69. 2.94
93. 1.5
117. 1
(hr)
22. 12
46. 12
70. 12
94. 12
118. 8
int
int
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23. 0.923
47. 0.315
71. 0.857
95. 1.06
119. 0.615
g-
------ mL
24. 2.01
48. 1.94
72. 2.01
96. 2.1
120. 2.2
g-
------ mL
25. 1.5
49. 1.74
73. 1.5
97. 1.5
121. 1.78
g
------ mL
26. 1.06
50. 1.55
74. 1.1
98. 1.01
122. 1.42
N
Cp
ss
max free
Cp
Cp
ss
avg free
ss
min free
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15.8.3
1. Dose = 500 mg (given)
2. Bioavailability (f) = 0.95 (given)
3. Unbound Fraction = 0.02 (given)
4. V d = 10L (given)
0.693
t1 2
5. k = ------------- = 0.0533hr
6. t 1 2 = 13hr (given)
f Dose
k Vd
Cl
Cl
15. Cl h
int
16. Cl r
int
Q Cl h
-----------------Q Cl
= ------------------h- = 26.5L hr
fu
Q Cl
-----------------rQ Cl
= ------------------r = 0.267L hr
fu
17. FR h = 1 (given)
18. FI h = 1 (given)
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19. FR r = 1 (given)
20. FI r = 1 (given)
21. F Cl = 1 (given)
22. = 12hr (given)
t1 2
24.
Cp
25.
Cp
ss
fu S f D
g1
= ------------------------- -------------------= 2.0 ------N
mL
V
max free
1
1 ---
2
ss
f u S f D fu S f D
g= -------------------------= ------------------------------ = 1.5 ------VK
V 0.693 N
mL
avg free
N
26.
Cp
ss
min free
1---
2
fu S f D
g= -------------------------- -------------------- = 1.1 ------N
mL
V
1 1---
2
27. Dose = mg
28. Bioavailability (f) = 0.95 (no change)
29. Unbound Fraction = 0.02 (no change - given)
30. V d = 10L (given)
0.693
t1 2
f Dose
k Vd
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39. Cl h
int
40. Cl r
int
Q Cl h
-----------------Q Cl
= ------------------h- = 26.5L hr
fu
Q Cl
-----------------rQ Cl
= ------------------r = 0.267L hr
fu
41. FR h = 1 (given)
42. FI h = 1 (given)
43. FR r = 1 (given)
44. FI r = 1 (given)
45. F Cl = 1 (given)
46. = 12hr (given)
t1 2
48.
Cp
49.
Cp
ss
fu S f D
1
g= ------------------------- -------------------= 2.0 ------N
V
mL
max free
1 1---
2
ss
f u S f D fu S f D
g= -------------------------= ------------------------------ = 1.5 ------VK
V 0.693 N
mL
avg free
N
50.
Cp
ss
min free
1---
2
fu S f D
g= -------------------------- -------------------- = 1.1 ------N
V
mL
1 1---
2
51. Dose = mg
52. Bioavailability (f) = 0.95 (no change)
53. Unbound Fraction = 0.02 (no change - given)
54. V d = 10L (given)
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0.693
t1 2
f Dose
k Vd
63. Cl h
int
64. Cl r
int
Q Cl h
-----------------Q Cl
= ------------------h- = 26.5L hr
fu
Q Cl
-----------------rQ Cl
= ------------------r = 0.267L hr
fu
65. FR h = 1 (given)
66. FI h = 1 (given)
67. FR r = 1 (given)
68. FI r = 1 (given)
69. F Cl = 1 (given)
70. = 12hr (given)
t1 2
72.
Cp
ss
fu S f D
1
g= ------------------------- -------------------= 2.0 ------N
V
mL
max free
1 1---
2
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73.
74.
Cp
Cp
ss
f u S f D fu S f D
g= -------------------------= ------------------------------ = 1.5 ------VK
V 0.693 N
mL
avg free
ss
min free
1--- N
2
fu S f D
g= ------------------------- -------------------- = 1.1 ------N
V
mL
1 1---
2
75. Dose = mg
76. Bioavailability (f) = 0.95 (no change)
77. Unbound Fraction = 0.02 (no change - given)
78. V d = 10L (given)
0.693
t1 2
f Dose
k Vd
87. Cl h
int
88. Cl r
int
Q Cl h
-----------------Q Cl
= ------------------h- = 26.5L hr
fu
Q Cl
-----------------rQ Cl
= ------------------r = 0.267L hr
fu
89. FR h = 1 (given)
90. FI h = 1 (given)
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91. FR r = 1 (given)
92. FI r = 1 (given)
93. F Cl = 1 (given)
94. = 12hr (given)
t1 2
96.
Cp
97.
Cp
ss
fu S f D
g1
= ------------------------- -------------------= 2.0 ------N
mL
V
max free
1
1 ---
2
ss
f u S f D fu S f D
g= -------------------------= ------------------------------ = 1.5 ------VK
V 0.693 N
mL
avg free
N
98. Cp
ss
min free
1---
2
fu S f D
g= -------------------------- -------------------- = 1.1 ------N
mL
V
1 1---
2
99. Dose = mg
100. Bioavailability (f) = 0.95 (no change)
101. Unbound Fraction = 0.02 (no change - given)
102. V d = 10L (given)
0.693
t1 2
f Dose
k Vd
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111. Cl h
int
112. Cl r
int
Q Cl h
-----------------Q Cl
= ------------------h- = 26.5L hr
fu
Q Cl
-----------------rQ Cl
= ------------------r = 0.267L hr
fu
113. FR h = 1 (given)
114. FI h = 1 (given)
115. FR r = 1 (given)
116. FI r = 1 (given)
117. F Cl = 1 (given)
118. = 12hr (given)
t1 2
120.
Cp
121.
Cp
ss
fu S f D
1
g= ------------------------- -------------------= 2.0 ------N
V
mL
max free
1 1---
2
ss
fu S f D f u S f D
g= -------------------------= ------------------------------ = 1.5 ------VK
V 0.693 N
mL
avg free
N
122. Cp
ss
min free
1---
2
fu S f D
g= -------------------------- -------------------- = 1.1 ------N
V
mL
1 1---
2
Basic Pharmacokinetics
REV. 99.4.25
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CHAPTER 16
Exam 3
Author:
Reviewer:
Basic Pharmacokinetics
REV. 99.4.25
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16-1
Exam 3
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) with antidepressant properties. After oral
administration, the drug is almost completely absorbed from the gastrointestinal tract, however despite complete
absorption, oral bioavailibiliity in man is approximately 50% on account of first-pass hepatic metabolism. Steady-state
plasma concentrations are achieved within 5 to 10 days after initiation of therapy and are 30 to 50 % higher than those
predicted from single dose data. Fluvoxamine displays non-linear steady state pharmacokinetics over the therapeutic
dose range, with disproportionally higher plasma concentrations with higher dosages. Plasma protein binding of fluvoxamine (77%) is low compared with that of other SSRIs.
V.L. is a 39 year old, 110# female suffering from severe depression. She was admitted to the hospital and prescribed 100mg BID of Fluvoxamine but still her depression was uncontrolled at this dose. Her plasma concentration
on this regimen was 20ug/L. After her physician increased her dose to 300 mg BID her plasma concentration was 500
ug/L. V.L.s depression was controlled at this dose, however she was complaining of adverse effects. The therapeutic
range (total drug ug/L) of fluvoxamine is 20-500. Fluvoxamine is metabolized extensively (93%) by the liver to an
inactive metabolite.
1.
2.
3.
4.
5.
The doctor would like to change her therapy in order to minimize side effects. What dose would you
recommend tolower her plasma concentration to 300 ug/L?
V.L. has major complications from a combined hepatitis B infection and cirrhosis of the liver. As a result her
protein binding is reduced to 66%, her K m changes to 0.03 mg/L and her V max changes to 100mg/day.
6.
What would be her plasma concentration of total fluvoxamine if she maintained the regimen from
question 5 (mg/L)?
7.
8.
What total fluvoxamine plasma concentration would you recommend achieving to get her free fluvoxamine plasma concentration back to that of the regimen in question 5 (mg/L)?
Basic Pharmacokinetics
REV. 99.4.25
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16-2
Exam 3
9.
What daily dose of fluvoxamine (by I.V. bolus) would you recommend to get her average free fluvoxamine
plasma concentration approximately back to what it was when she was healthy (mg/day)?
Vd
% Bound Drug
Healthy
Sick
0.15 L/kg
0.19L/kg
99.0%
97.0%
10.
11.
12.
13.
14.
15.
16.
17.
V.L. is now suffering from chronic renal insufficiency. Bound flurbiprofen has now decreased to 97%
ss
ss
ss
ss
19.
20.
What would her dose be now, if you wanted to maintain approximately the same free plasma concentrations as the previous therapy with the largest tau?
21.
The renal insufficiency clears up and she comes down with mono. Her plasma albumin drops to 50% of
normal thus reducing the bound fraction to 96%. What is her new hepatic clearance using the healthy V d ?
22.
What would her dose be now, if you wanted to maintain approximately the same plasma concentrations as
the previous therapy with the largest tau?
Basic Pharmacokinetics
REV. 99.4.25
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16-3
Exam 3
23.
The mono clears up, but now there seems to be hepatic stenosis. Her plasma flow is reduced to 50% of
normal. What would her dose be now, if you wanted to maintain approximately the same concentrations
as the previous therapy with the largest tau?
Clentiazem is a chlorinated analog of diltiazem. It is currently undergoing clinical evaluation for the treatment
of angina pectoris and hypertension. The primary mechanism responsible for the antihypertensive effect of CLZ is a
decrease in peripheral vascular resistance due to the blockade of calcium channels. The following information was
obtained from a dose of 20 mg Clentiazem given I.V.
Table 2:
37.52ng mL
A1
2.70hr
16.17ng mL
B1
0.078hr
k 10
0.243hr
k 12
1.67hr
k 21
0.868hr
AUMC
2729.6ng mL hr
1
1
1
1
2
24.
25.
26.
27.
28.
29.
30.
Basic Pharmacokinetics
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16-4
Exam 3
ss
31.
32.
33.
ss
ss
Any number from the answer pool may be used once, more than once, or not at all.
TABLE 2-1 Answer
Pool
A
B
C
D
E
F
G
H
I
J
A
B
C
D
E
F
G
H
I
J
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-1