Pharmacokinetics & Biopharmaceutics 201

School | PMB | Subject Area & Catalogue number | PHAR 2006 | Paper | 1 |

Course Name | Pharmacokinetics and Biopharmaceutics 201 |

Student ID | ||

Given Name/s | Surname | |

If you are required to use a calculator, please note the make and model here | Make | Model |

Official Reading Time: Writing Time: | 10 Minutes 2:00 |

Question | Marks |

1 | 35 |

2 | 30 |

3 | 20 |

4 | 15 |

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

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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) |

0.5 | 4.20 |

1 | 3.00 |

2 | 1.72 |

2.5 | 1.38 |

3.5 | 1.00 |

5 | 0.70 |

6 | 0.65 |

7 | 0.60 |

9 | 0.50 |

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)

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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)

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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)

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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)

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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)

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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:

Formulation | Dose (mg) | Route of Delivery | AUC (mg.L/h) |

A | 100 | intravenous | 20 |

B | 500 | intravenous | 100 |

C | 100 | oral | 19 |

D | 500 | oral | 120 |

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)

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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)

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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)

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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 Dose | F |

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)

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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