Professional Documents
Culture Documents
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.
ka –k t
C p = fD
– Kt
------ ⋅ --------------
- ⋅ (e – e a ) (EQ 5-18)
Vd k a – K
ln ( k a ⁄ K )
t p = ----------------------- (EQ 5-21)
( ka – K )
X
-----a- = K ⋅ AUC ∞ – ( C p + K ⋅ AUC t ) (EQ 5-22)
v
f = the absolute bioavailabilty; the fraction of dose which ultimately reaches sys-
temic 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))
7.1.2 UTILIZATION
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
µg
MEAN SERUM LEVEL --------
Time (hr) 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
g. Cl
h. Vd
j. Cp max
The data was plotted as above with the best fit line drawn. From the graph the fol-
lowing parameters were derived:
A B
1 70.0 77.1
2 79.5 82.3
3 80.7 69.4
4 68.6 60.6
6 49.4 48.0
8 35.0 33.7
12 15.3 17.4
24 2.1 3.0
Calculate peak time and Cp max and AUC for both products.
Answer:
A B C D
1 1.79 6 0.45
2 1.36 12 0.08
4 0.78
Why/Why not?
g} How long would it take that infusion rate to attain a therapeutic plasma con-
centration of 0.5 mic/ml ?
Answer:
IV Bolus Parameters:
Cp max2.4 mic/mL
AUC 8.5
K 0.283 hr^-1
5/2/8.5 = 0.61
Very well. Only 61% (f) of liquid gets in and you would expect only 77% of that to
show up in the urine because only 77% of the IV dose shows up in the urine
(.61*.77=.47).
f} How long would it take that infusion to attain a therapeutic plasma concentra-
tion of 0.5 mic/ml ?
a) Find ka
5.5 33 1.5 65
4.1 40 1.1 80
2.9 52
If 100 mic dose were given by IV bolus, how long would it be before the volunteer
would regain 80% of his control?
Answwer:
T max 1.7 hr
AUC (trap)30.07
K 0.225 hr^-1
Ka 1.22 hr^-1
f (AUCoral/Doseoral)/(AUCiv/Doseiv) = .98
dR/dln(c) = 27.86
100 mic dose IV yields Cp0 of (Cp0 =AUC * K = 20.4 * 0.225) 4.59ng/mL.
T = 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.
Answer:
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.
g) Tetracycline has a pKa of 9.7. Tetracyclines tend to localize in the dentin and
enamel of developing teeth causing hypoplasia and permanent discoloration of
teeth. Would you recomend tetracyline for a 110 pound lactating mother ?
Support your argument with the dose of the child. (Child's weight 11 lbs. and he
eats 2 oz of milk every 2 hours. Mom's average plasma concentration is main-
tained at 3 mic/ml by taking 250 qid. pH of the milk is 6.1, pH of blood is 7.4)
Answer:
Pharmacokinetic parameters:
Lederle Mylan IV
Ratio of bioequivalence parameters (Cpmax, Tmax and AUC) are all within guide-
lines. So, the would be considered bioequivalent.
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
Answer:
With only one data point in the early time points, the larger rate constant is in ques-
tion. 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
kr = K - km = 0.085 hours^-1
Answer:
AUC (mg/L)*hr117.8
K (hr^-1) 0.096
ka (hr^-1) 2.11
f = (AUCoral/DOSEoral)/(AUCiv/DOSEiv) =
Vd
AUC * K = Cp0iv
Infusion rate = Q = Cpss * TBC = 15 mg/L * 2.83 L/hr = 42.45 mg/hr Theophyl-
line = 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.
Answer:
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
1 1.79
2 1.36
4 0.78
6 0.45
12 0.08
a} find K, Cp0.
Both can be found from the graph. K = .283/hr Cp0 = 2.36 mic/ml
5.2/8.5 = 0.61
Very well. Only 61% (f) of liquid gets in and you would expect only 77% of that
to show up in the urine because only 77% of the IV dose shows up in the urine
(0.61 * .77 = .47).
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 concen-
tration of 0.5 mic/ml ?
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.
Roxane Lilly
1 .42 .58
2 .73 .77
3 .71 .74
4 .61 .66
6 .45 .52
8 .32 .34
12 .20 .22
Answers
0.5 -- 50
1 -- 77
1.5 -- 100
2 29 100
3 24 90
4 18 78
5 15 59
6 11 45
7 9 32
a) find ka
c) Calculate TBC
w/o w
a) Calculate TBC
c) Calculate the effect on total body clearance in a patient with viral hepititis (FI =
0.3).
(.517)(18.8) = 9.72
d) Calculate the effect on total body clearance in a patient with stenosis (FR = 0.3).
The patient with viral hepatitis would need modification in therapy. Because
of the decrease in TBC, we can see that the drug is staying the body much
longer than normal, therefore the dosage regimen should be decreased.
(hours) Hygroton@Generic
.5 0.14 0.15
1 0.51 0.64
2 1.23 1.67
3 1.94 2.48
4 2.20 2.91
6 2.64 3.49
8 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
Pharmacokinetic parameters
Ka (hr^-1)0.168 0.253
Ke (hr^-1)0.019 0.019
blood presure
(336/50mg)/(293/50mg) = 1.15
No. The maximum concentration the generic is too much greater than that of
the brand name product.
R(G/H)
AUC (0 to inf)115 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 Gam-
mans (Am J Med:80(supp 3b),41-51;1986):
0.25 -- 1.07
2 2.80 2.51
3 2.10 2.05
4 1.57 1.60
6 0.8 0.91
a) find ka
answer:
IV Oral
ka (hr^-1) 1.3
= 0.04
Time(Hr.)Formulation BFormulation A
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
2) Five hundred mg of valproate was administered by IV bolus. The AUC for that
route was 574 mg/L * hr. Calculate f for formulation A. Calculate Cp0 for the IV
dose.
need to respond to another health professional who asked you to stock that formu-
lation for his patients.
Answers:
Formulation B R(A/B)
ka = 0.493 hr^-1
K = 0.0655
cpmax =
(ka/(ka-k))*(fX0/Vd)*(exp(-k*tmax)-exp(-ka*tmax)
13.3 mg/L
= (287/250)/(574/500)
= 1.0
The following data was made available by Lederle Labs regarding its generic
Procainamide HCl. (Dose 250mg).
g) Would you recommend your patient breast feed her newborn? Prepare a short
consult for her physician. Support your argument with the dose of the child.
(Child's weight 11 lbs. and he eats 2 oz of milk every 2 hours. Mom's average
plasma concentration is maintained at 4 mic/ml from a 1 g dose ever 6 hours. pH of
the milk is 6.3, pH of blood is 7.4)
j) Calculate the effect on her total body clearance if she were to contract viral hep-
atitis which effect liver function (FI = 0.4). Prepare a short consult for her physi-
cian as to whether you would recommend a change in therapy. d) Calculate the
effect on her total body clearance stenosis of the liver (FR = 0.4). Prepare a short
consult for her physician as to whether you would recommend a change in therapy.
Answers:
IV LederleSquibb R(L/S)
t lag 0 0 0.24
= 7.4 / 8.57
= 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:
Formula AFormula B
Time Cp Cp Cp
1 42.1 43.7
3 36.2 25.5
4 65.6 27 20.7
12 1.5 1.0
d} Can you conclude that these products are bioequivalent ? (you must support you
argument)
Answers:
IV A B R(A/B)
=(219.7/10)/(785/25)
=0.7
Tetracycline HCl has a pKa of 9.7. Tetracyclines tend to localize in the dentin and
enamel of developing teeth causing hypoplasia and permanent discoloration of
teeth. Would you recommend tetracycline for a lactating mother ? Support your
argument with the dose of the child. (Child's weight 11 lbs. and he eats 2 oz of
milk every 2 hours. Mom's average plasma concentration is maintained at 4 mic/
ml she is taking 250 mg T.I.D. ( Milk pH = 6.1, Blood pH = 7.4)
57.6mg/5kg = 11.52mg/kg = dose that the child is getting from the mother's
milk.
I would not recomend tetracycline for a lactating mother. The dose that a nurs-
ing 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
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. Pre-
pare a short consult for her physician in which you might (or might not) recom-
mend the patient stop breast feeding while she is on this medication. Include
appropriate calculations.
This dose is much greater then that given to the mother. The mother should
discontinue breast feeding while taking Oxazepam.
Bioequivalence studies are sometimes done within the same company to check if
the tablets of the same drug, but different strengths (with the strength normalized)
could be considered equivalent (i.e. could two 5 mg tablets be considered equal to
one 10 mg tablet). While not strictly kosher (products are not pharmaceutical
equivalents because of different strengths), it is done. Here is the results of such a
study in which Zomax 100 and 200 mg tablets were compared. (Yes, I know that
Zomax was removed from the market after a short life of only 6 months.)
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
(7.48/100)/(4.25/50) = 0.88
(16.9/200)/(4.25/50) = 1
10) What is the absorption rate constant for the 100 mg tablet ?
11) What is the intercept of the extrapolated line for the 200 mg tablet ?
12) What is the absorption rate constant for the 200 mg tablet ?
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
16) What infusion rate would you recommend to maintain an average plasma con-
centration of 1 mic/ml ?
17) What would be the concentration (mg/L) 2 hrs after discontinuing the infu-
sion assuming you reached steady state ?
= 1mg/L * e(-0.4 * 2)
= 0.44
A 110 pound mother breast feeds her 11 pound infant while on morphine sulfate
(base, pKa = 9.85). Mother's average circulating plasma levels are 0.5 ug/ml fol-
lowing a 10 mg IV dose q4h. (pH Milk = 6.1, pH blood = 7.4)
18) What is the Ratio of morphine concentration in the milk as compared to the
blood ?
= 20
19) How much (mg) morphine is contained in 120 cc of breast milk (the child con-
sumes 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.
Answers:
IV Tablet Tablet
Answers are rounded off. When you pick a foil, use that number in subsequent cal-
culations 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 B C B
Time (hours)
AUC(0->inf)53.957.7
(mic/mL*hr)
Cp max10.6 9.9
Ka (hr^-1)2.66
Cp0 = AUC * K
= 39.8 * 0.25
= 9.95
Vd = D/Cp0
= 400mg/(9.95mg/L)
= 40.2 L
3) What is the half life for rifampin (hr)? *a) 2.8 b) 2.3 c) 2.0 d) 1.75 e)
1.5
t1/2 = .693/0.25
= 2.77
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
5) Calculate the AUC (0->1hr) for C (mic/mL*hr). a) 1.95 *b) 3.9 c) 7.8 b)
8.9 e) 17.8
0.5/0.25 = 2
8) Calculate the absolute bioavailability for the generic product. a) 0.70 *b)
0.95 c) 1 d) 1.05 e) 1.43
(57.7/600)/(39.8/400) = 0.966
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
11) Calculate the peak time for the generic product (min). a) 37 b) 67 c) 86 d)
91 e) 105
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). a) 37 *b) 59 c)
86 d) 95 e) 105
tp = [ln(2.66/0.25)]/(2.66 - 0.25)
= 0.98 hr = 59 min
*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 require-
ments.
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
= 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)?
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 infu-
sion 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
Q = Cpss * K * Vd
= 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
= 2.5 * 39.9
= 100mg
19) While Rifampin is not administered by IV infusion, what would be the infu-
sion rate necessary to obtain a plasma concentration of 2.5 mg/L in about 2.5 to 3
hours (mg/hr)? a) 25 *b) 50 c) 100 d) 150 e) 200
= 50 mg/hr
Answers:
A B IV
(1) Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:
(2) For each of the following pairs of variables (ordinate against abscissa), draw
a graph illustrating the qualitative profile of their relationship. Where appropri-
ate, 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. Graphs are for a
drug given by oral route where applicable.
a} total amount of drug collected minus the amount collected at the time in the
urine vs time
SECTION I
(1) Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:)
(3) For each of the following pairs of variables (ordinate against abscissa), draw
a graph illustrating the qualitative profile of their relationship. Where appropri-
ate, 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. Graphs are for a
drug given by oral route where applicable.
SECTION I
1. Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:
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 specifi-
cally indicate on your plot that semi-log paper is being considered (write "SL"), it
will be assumed that rectilinear paper is being considered.
AUC vs ka
AUC vs ke
SECTION I
1. Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:
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 specif-
ically 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.
AUC vs ka
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 specif-
ically indicate on your plot that semi-log paper is being considered (write "S-L"),
it will be assumed that rectilinear paper is being considered
SECTION I
1. Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:
a) Bioequivalance
b) Intrinsic Clearance
e) f
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 specif-
ically indicate on your plot that semi-log paper is being considered (write "S-L"),
it will be assumed that rectilinear paper is being considered
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
SECTION I
1. Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:
a) Henderson-Hasselbach relationship
b) Therapeutic alternatives
c) Therapeutic equivalents
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 you specifi-
cally indicate on your plot that semi-log paper is being considered (write "SL"), it
will be assumed that rectilinear paper is being considered
SECTION I
1. Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:
a) Henderson-Hasselbach relationship
b) Therapeutic alternatives
c) Therapeutic equivalents
d) Comparative bioavailability
e) Absolute bioavailability
f) Bioequivalents
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
I. therapeutic moieties
I. pharmaceutical alternatives
III. bioequivalents
6) The Federal guidelines for for bioequivalence require that the following phar-
macokinetic parameters be within + 20 % of
II. Ka, Ke
III. Vd
8) The peak time of a drug given by the oral route is dependent on:
9) The slope of the terminal portion of the graph of the metabolite of a drug which
(the drug, not the metabolite) was given
I. AUC (0 to Inf)
III. Cpmax
Where the are only three foils (possible quesses), please use K type system:
A) I ONLY
B) III ONLY
C) I AND II ONLY
I Infusion rate
I Infusion rate
II time
3) When calculating the AUC for an oral product using the trapezoidal rule, con-
centrations necessary to calculate the
I the intercept of the extrapolated line of the plasma vs. time profile.
4) When calculating the AUC for an IV product using the trapezoidal rule, con-
centrations necessary to calculate the
I the intercept of the extrapolated line of the plasma vs. time profile.
7) When plotting the Wagner-Nelson function vs. time, a plot which proceeds hor-
izontally for a measurable time and then
declines:
III is an indication of a delay in release of the drug from the delivery system, a lag
time.
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
II 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
II one.
Cyclosporine A (Problem 8 - 6)
Quigano, R., et al., "Effect of atropine of gastrointestinal motility and the bioavailability of cyclosporine A in rats", Drug Metabo-
lism 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 gath-
ered 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:
AUC -------
ug- ⋅ hr
mL
AUMC -------
ug- ⋅ hr 2
mL
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0 --------
ug
mL
Vd (L)
Cp at 1 hour -------
ug-
mL
Cpmax --------
ug
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
1. MRT iv
3. t1 ⁄ 2
4. Cp 0
5. Vd
6. The plasma concentration ( Cp ) of cyclosporine A at 1 hour after the iv dose was given.
13. Cp max , the maximum concentration of the oral dosage form given as a single dose.
Fosinopril (Problem 8 - 7)
Gehr, T., et al., "The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients", European Journal of Clin-
ical 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 pharmaco-
logically active metabolite, fosinoprilate (MW 435.2). About 50% of the drug is excreted unchanged through the kid-
neys. 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.
AUC -------
ug- ⋅ hr
mL
AUMC -------
ug- ⋅ hr 2
mL
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0 -------
ug-
mL
Vd (L)
Cp at 1 hour --------
ug
mL
Cpmax --------
ug
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
1. MRT iv
3. t1 ⁄ 2
4. Cp 0
5. Vd
6. The plasma concentration ( Cp ) of fosinopril at 1 hour after the iv dose was given.
13. Cp max , the maximum concentration of the oral dosage form given as a single dose.
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.
AUC -------
ug- ⋅ hr
mL
AUMC -------
ug- ⋅ hr 2
mL
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0 --------
ug
mL
Vd (L)
Cp at 1 hour -------
ug-
mL
Cpmax --------
ug
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
1. MRT iv
3. t1 ⁄ 2
4. Cp 0
5. Vd
6. The plasma concentration ( Cp ) of verapamil at 1 hour after the iv dose was given.
Zidovudine (Problem 8 - 9)
Trang, J., et al., "Zidovudine bioavailability and linear pharmacokinetics in female B6C3F1 mice", Drug Metabolism and Disposi-
tion Vol, 21 (1993), p.189 - 193.
Zidovudine (AZT) is a potent inhibitor of HIV-1 during viral replication. It has been approved for the treat-
ment 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:
AUC -------
ug- ⋅ hr
mL
AUMC -------
ug- ⋅ hr 2
mL
MRT (hr)
MAT (hr)
ke (hr-1)
ka (hr-1)
Cp0 --------
ug
mL
Vd (L)
Cp at 1 hour -------
ug-
mL
Cpmax --------
ug
mL
Tmax (hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
1. MRT iv
3. t1 ⁄ 2
4. Cp 0
5. Vd
6. The plasma concentration ( Cp ) of zidovudine at 1 hour after the iv dose was given.
13. Cp max , the maximum concentration of the oral dosage form given as a single dose.