Pharmacokinetics and Biopharmaceutics 201

Pharmacokinetics & Biopharmaceutics 201

SchoolPMBSubject Area & Catalogue numberPHAR 2006Paper1
Course NamePharmacokinetics and Biopharmaceutics 201
Student ID
Given Name/sSurname
If you are required to
use a calculator, please
note the make and
model here
MakeModel
Official Reading Time:
Writing Time:
10 Minutes
2:00
QuestionMarks
135
230
320
415

Instructions to Candidates:
Answer all questions.
Show all calculations and assumptions in the answer book.
Write your name and Student ID number on all loose graph papers.
Equation Sheet is attached
Permitted Materials
• Non-programmable calculator
DO NOT COMMENCE WRITING UNTIL INSTRUCTED TO DO SO
Page 1 of 12
Pharmacokinetics & Biopharmaceutics 201
Question 1
A 20 year old healthy male volunteer (70 kg) is given a 100 mg intravenous injection of a new drug
during Phase 1 clinical trials. Plasma samples at various time points are provided below. Urine was
also collected for 40 hours and found to contain 80 mg of unchanged drug. Pre-clinical studies
indicate that there is negligible binding to plasma proteins.

Time (h)Plasma Concentration (mg/L)
0.54.20
13.00
21.72
2.51.38
3.51.00
50.70
60.65
70.60
90.50

i. Plot the data on the graph paper provided.
(5 Marks)
ii. Derive the equation that describes the plasma concentration following the intravenous dose.
(5 Marks)
iii Calculate the plasma clearance of the drug.
(3 Marks)
Page 2 of 12
Pharmacokinetics & Biopharmaceutics 201
iv Calculate the Initial Volume of Distribution (Vi) of the drug.
(3 Marks)
v Calculate the Terminal Volume of Distribution (Vd) of the drug.
(3 Marks)
vi Briefly explain the difference between these values.
(3 Marks)
vii Explain why a young healthy male was used in this study.
(3 Marks)
Page 3 of 12
Pharmacokinetics & Biopharmaceutics 201
viii Another volunteer in a subsequent trial is given the same dose but starts to demonstrate
signs of toxicity. Following appropriate calculations discuss whether administering a
diuretic to increase urine flow rate will be useful in this situation.
(10 Marks)
Page 4 of 12
Pharmacokinetics & Biopharmaceutics 201
Question 2
An antibiotic is being used for the treatment of serious infections caused by Gram positive bacteria.
Such infections include pneumonia, plus skin and soft tissue infections. It is administered by
intermittent intravenous doses. The antibiotic is available in glass vials containing 20 mL of the
antibiotic at a concentration of 50 mg/mL in 0.9% NaCl. It is usually given as a bolus dose over 5
min (assume this is negligible compared to the interval between doses).
The clearance of the antibiotic with respect to concentrations in plasma has been reported to be
around 2.2 mL/min/kg while its volume of distribution is approximately 0.85 L/kg. The fraction of
an intravenous dose excreted unchanged in urine is about 0.35; the fraction after an oral dose is
0.33. Its fraction unbound in plasma is 0.85.
Concentrations of the antibiotic above values of 2 μg/mL are required in plasma for almost the
entire dosing interval for effective therapy. Concentrations approaching 50 μg/mL incur a greater
risk of unacceptable toxicity; more common signs include hepatotoxicity (hence the need for
regular monitoring of indicators of liver dysfunction in plasma during therapy), and reduced
numbers of red blood cells, leukocytes and neutrophils.
i. Calculate an appropriate/sensible/convenient intravenous dosage regimen for the antibiotic
for treating a 65 kg male over 10 days.
(20 Marks)
Page 5 of 12
Note from Dr Foster: this question tends to use somewhat vague language around the
targets. I will not be vague: if you are competent you should be able to very clearly
understand what is expected of you.
In this Q:
I suggest targeting 2ug/mL and 50ug/mL for your window. Stay inside the window.
This question also has an issue where if you target the Css,ave of 25-26 ug/mL, then
the Cmax,ss and Cmin,ss will be marginally outside the window even if you choose a
“good” dose interval. However, targeting this Css,ave uses a “wasteful” amount of a
vial. So using a less wasteful amount of vials results in a slightly lower Css,ave but the
Cmax,ss and Cmin,ss will be satisfactory. This is something we can discuss in class.
If you follow the proceedures you have been taught, then any dose regimen design
question I present to you will will work out very nicely.
Pharmacokinetics & Biopharmaceutics 201

ii.What conclusion would you make on the bioavailability of the antibiotic after
oral administration? Explain fully, using calculations if appropriate.

(4 Marks)
iii What, if any, adjustment would you make to the dosing regimen if during treatment it was
found that the renal clearance of the antibiotic was reduced by an estimated 50%. Justify
your decision.
(6 Marks)
Page 6 of 12
Pharmacokinetics & Biopharmaceutics 201
Question 3.
Prostudy is a highly soluble drug marketed to enhance memory recall in pharmacy students. It’s
fraction excreted (fe) is approximately 30%. Recently it has become apparent that Prostudy is
inactive but it does have an active metabolite (studyme) that is responsible for its beneficial effects.
The pharmacokinetics of Prostudy from 4 different formulations are summarised in the table below:

FormulationDose (mg)Route of DeliveryAUC (mg.L/h)
A100intravenous20
B500intravenous100
C100oral19
D500oral120

i. From the data provided, calculate the apparent bioavailability of formulations C and D
(4 Marks)
ii Provide a logical explanation for the observed bioavailabilities of formulations C and D
(8 Marks)
Page 7 of 12
Note from Dr Foster: this question will result in you obtaining an unusual
bioavailbility for formulation D. The F cannot exceed 100%, as you know, which is
why they used the word “apparent” and in the next Q ask you for an explanation.
This would be very unexpected for students, and the explanation is very complex.
I would be very unlikely to pose such a question.
Feel free to have a go, and post on the discusson board, or at the exam review sessions
and we can talk about it ?
Pharmacokinetics & Biopharmaceutics 201
iii Knowing that Prostudy exerts its effects through the active metabolite, studyme, which of the
4 formulations (A,B,C,D) do you expect to be the most effective (per mg of parent drug
administered). Explain your answer.
(8 Marks)
Page 8 of 12
Pharmacokinetics & Biopharmaceutics 201
Question 4
i. Outline the factors (both physiological and physico-chemical) that may impact on the
amount of drug absorbed following an oral dose.
(10 Marks)
ii. Highlight 5 ways in which these factors might be overcome/modified through the use of
different pharmaceutical formulations.
(5 Marks)
Page 9 of 12
Pharmacokinetics & Biopharmaceutics 201
Equations and physiological values
Glomerular filtration rate = 120 mL/min
Hepatic blood flow = 1.5 L/min
Renal blood flow = 1.2 L/min
Cardiac output = 5 L/min
Haematocrit = 0.5
Plasma concentrations after an intravenous bolus
– monoexponential C = C(0).exp-k.t
– biexponential C = A.exp-α.t + B.exp-β.t
Plasma concentrations during an intravenous infusion (monoexponential only)
C = (Ro/CL).(1-exp(-k.t))
where Ro is the zero-order infusion rate
Plasma concentrations after an extravascular dose
[ ] tk tka
kkaVd
kaDoseF
C . expexp .
).(
..
– –


=
Half-life and elimination rate constant
k = Cl
Vd
t½ = ln2
k
k = – ln(Cp2/Cp1)
t2 – t1
Physiological determinants of clearance and volume of distribution

CL=Dose. F /AUC
Hepatic clearance
CLHb=QH

f .CL
Q + f .CL
u int
H u int
⎛⎜⎝
⎞⎟⎠
Renal clearance
CLR =
⎛⎜⎝
⎞⎟⎠
fu
.GFR +
QR.fu.CLI
QR + fu.CLI (1-FR)
Page 10 of 12
Pharmacokinetics & Biopharmaceutics 201
Volume of distribution

T
T
fu
P
Pharmacodynamic response

fu
+= VVVd
nn
n
CEC
CE
E
+
=
50
max .
Accumulation Index
⋅- τ

=
A k
Ass
exp1
1
1max,
max
Oral dosing equations
Loading Dose = Vd Cp
LD F

Incremental= Vd (Cp desired – Cp initial)
Loading DoseF

Average steady-state = F Dose/τ
plasma concentration Cl
(Cpssave)

Cpssmax =(Dose) (F)
(Vd) (1-e-kτ )
Cpssmin =(Dose) (F) x e-kτ
(Vd) (1-e-kτ)

Creatinine Clearance (CrCl)

CrCl (mL/min) =(140-Age) x LBW (kg) x F
Serum Creatinine (micromol/L)

F= 1.23 (males) or 1.04 (females)
Page 11 of 12
Pharmacokinetics & Biopharmaceutics 201
Bioavailability
F = (AUC)oral x Dose iv
(AUC)iv x Dose oral
Non-linear Equations

(F) (Dose/τ) =(Vm) (Cpss ave)
Km + Cpss ave
Cpssave=(Km) [(F) (Dose/τ)]
Vm – (F) (Dose/τ)

Page 12 of 12

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