CHAPTER-I

CLINICAL
PHARMACOKINETICS

BY
Prof. C.Ramasamy,
Head, Dept of Pharmacy Practice
SRM College of Pharmacy,
SRM University
 HOW TO USE THIS POWERPOINT
PRESENTATION

ƒThis supplements the other course material

ƒYou can view it on line or download it to your
computer and view it without being connected
to the internet.
ƒWork through the presentation at the start of
the course and note any issue which are not
clear.
ƒRead up on areas that you are not familiar
with and revisit the presentation from time to
time.
ƒTry the powerpoint based exercises
 WHAT IS CLINICAL
PHARMACOKINETICS ?
ƒStudy of the time course of a drug’s
movement through the body.

ƒUnderstanding of what the body does

to (or with) the drug.

ƒApplication of Therapeutic Drug

Monitoring (TDM) and
individualisation of drug therapy.
 OUTLINE

ƒReview of Concepts
ƒ Clearance, K, Half-Life, Volume of Distribution
ƒTherapeutic drug Monitoring

ƒPharmacokinetic Drug Interactions

ƒCases

ƒDiscussion/Questions
 PHARMACOKINETICS (PK) &
PHARMACODYNAMICS (PD)

ƒ PK - What the body does to the drug?

ƒ Absorption; distribution, metabolism, excretion (ADME)

ƒ PD - What the drug does to the body?

ƒ Drug concentration at the site of action or in the plasma is
related to a magnitude of effect
 PHARMACOKINETICS (PK) AND
PHARMACODYNAMICS (PD)

Plasma Site
Dose Concen- of Effects
tration Action

PK PD
 PHARMACOKINETICS VS
PHARMACODYNAMICS…CONCEPT

ƒ Fluoxetine increases plasma concentrations of amitriptyline.

This is a pharmacokinetic drug interaction.

ƒ Fluoxetine inhibits the metabolism of amitriptyline and

increases the plasma concentration of amitriptytline.
 PHARMACOKINETICS VS
PHARMACODYNAMICS…CONCEPT

ƒIf fluoxetine is given with tramadol serotonin

syndrom can result. This is a
pharmacodynamic drug interaction.

ƒFluoxetine and tramadol both increase

availability of serotonin leading to the
possibility of “serotonin overload” This
happens without a change in the
concentration of either drug.
 BASIC PARAMETERS

ƒIn the next few slides the basic concepts and

paramaters will be described and explained.

ƒIn pharmacokinetics the body is represented

as a single or multiple compartments in to
which the drug is distributed.

ƒSome of the parameters are therefore a little

abstract as we know the body is much more
complicated !
Volume of Distribution, Clearance and
Elimination Rate Constant
V

Volume 100 L

Clearance
10 L/hr
Volume of Distribution, Clearance and
Elimination Rate Constant
V
V2
Cardiac and
Skeletal Muscle

Volume 100 L (Vi)

Clearance
10 L/hr
 V2
Cardiac and
Skeletal Muscle
V
Volume 100 L (Vi)

Clearance
10 L/hr

Volume of Distribution =

Dose_______
Plasma Concentration
 V2
Cardiac and
Skeletal Muscle
V
Volume 100 L (Vi)

Clearance
10 L/hr

Clearance =
Volume of blood cleared of drug per unit time
 V2
Cardiac and
Skeletal Muscle
V
Volume 100 L (Vi)

Clearance
10 L/hr

Clearance = 10 L/hr
Volume of Distribution = 100 L
What is the Elimination Rate Constant (k) ?
 CL = kV
k = 10 Lhr -1 = 0.1 hr -1
100 L

10 % of the “Volume” is cleared (of drug) per hour

k = Fraction of drug in the body removed per hour
 CL = kV
If V increases then k must decrease as
CL is constant
 IMPORTANT CONCEPTS

ƒ VD is a theoretical Volume and determines the loading dose

ƒ Clearance is a constant and determines the maintenance
dose
ƒ CL = kVD
ƒ CL and VD are independent variables
ƒ k is a dependent variable
 VOLUME OF
DISTRIBUTION
Apparent volume of distribution is the theoretical volume that
would have to be available for drug to disperse in if the
concentration everywhere in the body were the same as that
in the plasma or serum, the place where drug concentration
sampling generally occurs.
 VOLUME OF DISTRIBUTION

ƒ An abstract concept

ƒ Gives information on HOW the drug is distributed in the

body

ƒ Used to calculate a loading dose

 Loading Dose

Dose = Cp(Target) x VD
 QUESTION

ƒ What Is the is the loading dose required fro drug A if;

ƒ Target concentration is 10 mg/L
ƒ VD is 0.75 L/kg
ƒ Patients weight is 75 kg

ƒ Answer is on the next slide

 ANSWER: LOADING DOSE OF DRUG
A

ƒDose = Target Concentration x VD

ƒVD = 0.75 L/kg x 75 kg = 56.25 L
ƒTarget Conc. = 10 mg/L
ƒDose = 10 mg/L x 56.25 L
ƒ = 565 mg
ƒThis would probably be rounded to 560 or
even 500 mg.
 CLEARANCE
ƒ Ability of organs of elimination (e.g. kidney, liver to “clear”
drug from the bloodstream
ƒ Volume of fluid which is completely cleared of drug per unit
time
ƒ Units are in L/hr or L/hr/kg
ƒ Pharmacokinetic term used in determination of maintenance
doses
 MAINTENANCE DOSE
CALCULATION

ƒMaintenance Dose = CL x CpSS av

ƒCpSS av is the target average steady state

drug concentration

ƒThe units of CL are in L/hr or L/hr/kg

ƒMaintenance dose will be in mg/hr so for

total daily dose will need multiplying by 24
 QUESTION

ƒ What maintenance dose is required for drug A if;

ƒ Target average SS concentration is 10 mg/L
ƒ CL of drug A is 0.015 L/kg/hr
ƒ Patient weighs 75 kg

ƒ Answer on next slide.

 ANSWER

ƒMaintenance Dose = CL x CpSS av

ƒCL = 0.015 L/hr/kg x 75 = 1.125 L/hr

ƒDose = 1.125 L/hr x 10 mg/L

= 11.25 mg/hr

ƒSo will need 11.25 x 24 mg per day

= 270 mg
 HALF-LIFE AND K

ƒ Half-life is the time taken for the drug concentration to fall to

half its original value
ƒ The elimination rate constant (k) is the fraction of drug in
the body which is removed per unit time.
Drug Concentration
C1

Exponential decay
dC/dt ∝ C
= -k.C
C2

Time
 Log Concn.
C0

C0/2
t1/2

t1/2

t1/2

Time
Time to eliminate ~ 4 t1/2
Integrating:
Cp2 = Cp1 .e-kt

Logarithmic transform:
lnC2= lnC1 - kt
logC2 = logC1 - kt/2.303
Elimination Half-Life:
t1/2 = ln2/k

t1/2 = 0.693/k
 STEADY-STATE
ƒSteady-state occurs after a drug has been
given for approximately five elimination
half-lives.
ƒAt steady-state the rate of drug
administration equals the rate of
elimination and plasma concentration -
time curves found after each dose should
be approximately superimposable.
Accumulation to Steady State
100 mg given every half-life

194 … 200
187.5
175
150

100

97 … 100
87.5 94
75
50
C
Cpav

Four half lives to reach steady state

 WHAT IS STEADY STATE (SS) ?
WHY IS IT IMPORTANT ?

ƒ Rate in = Rate Out

ƒ Reached in 4 – 5 half-lives (linear kinetics)

ƒ Important when interpreting drug concentrations in TDM or

assessing clinical response
THERAPEUTIC DRUG
Some
MONITORING
Principles
 THERAPEUTIC INDEX

ƒ Therapeutic index = toxic dose/effective dose

ƒ This is a measure of a drug’s safety

ƒ A large number = a wide margin of safety
ƒ A small number = a small margin of safety
DRUG CONCENTRATIONS MAY BE
USEFUL WHEN THERE IS:
z An established relationship between
concentration and response or toxicity
z A sensitive and specific assay
z An assay that is relatively easy to perf
z A narrow therapeutic range
z A need to enhance response/prevent
toxicity
 WHY MEASURE
DRUG CONCENTRATIONS?
ƒ Lack of therapeutic response
ƒ Toxic effects evident
ƒ Potential for non-compliance
ƒ Variability in relationship of dose and
concentration
ƒ Therapeutic/toxic actions not easily
quantified by clinical endpoints
POTENTIAL FOR ERROR WHEN
USING TDM
ƒ Assuming patient is at steady-state
ƒ Assuming patient is actually taking the drug
as prescribed
ƒ Assuming patient is receiving drug as prescribed
ƒ Not knowing when the drug concentration was measured in
relation to dose administration
ƒ Assuming the patient is static and that changes in
condition don’t affect clearance
ƒ Not considering drug interactions