Pharmacokinetics & Biopharmaceutics 201

November 2003

DIVISION OF --HEALTH SCIENCES--

SCHOOL OF PHARMACY AND MEDICAL SCIENCES-Subject Area: Pharmacy Catalogue Number:

010951

PHARMACOKINETICS AND BIOPHARMACEUTICS 201

Examination Day: Thursday Examination Time: 6-8pm

Examination Date: 18th Nov 2004 Length of Exam: 2 h

Student Name: ____________________________________ Student ID: _____________________________

Instructions to Candidates Answer all questions in the spaces provided. Calculators may be used Graph paper is provided. Please write your name on the graph paper. A list of symbols and equations is provided at the back of the exam. The mark allocated to each question is shown in the table below. Ensure that your answers are in the correct units. For examiners use only Question 1 2 3 4 5 Value 30 12 10 24 24 Mark

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Pharmacokinetics & Biopharmaceutics 201

November 2003

Question 1. The following data was obtained following administration of a single intravenous dose (200 mg) of a new drug Drug A.

Time after injection (hours) 0.5 1 2 4 6 10 15

Plasma concentration (mg/L) 6.9 5.4 3.6 2.2 1.5 0.8 0.35

Urine was collected for 24 hours after the dose and was found to contain 30 mg of unchanged drug. The fraction unbound in plasma was 0.15 and this was independent of concentration (0.1 to 10 mg/L). The blood-to-plasma concentration ratio was 0.8. (a) Plot the data, and (b) Calculate the following pharmacokinetic parameters (i) Elimination half-life hours

(ii)

The initial Volume of distribution (referenced to plasma)

(iii)

The terminal Volume of distribution (referenced to plasma)

L/h (iv) Clearance (referenced to plasma)

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Question 1 (continued) (v) Renal extraction ratio

(c) Determine the equation that describes the plasma concentration versus time profile of the drug after intravenous administration.

(d)What is the bioavailability of the intravenous drug?

(e) Calculate the maximum possible oral bioavailability of the drug.

(f) Briefly describe how you could assess actual oral bioavailability.

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Question 2. Procainamide is an antiarrhythmic agent with a narrow therapeutic index (4 to 8 mg/L). It has the following pharmacokinetic properties: Vd = 2 L/kg Renal Clearance = 3 x Creatinine Clearance Non Renal Clearance = 0.23 L/kg/h

As a pharmacist working on a cardiac ward, you have been asked to calculate an intravenous loading dose and a maintenance dose for a 50 kg (non-obese) male patient (age 80) experiencing a cardiac rhythm problem. His most recent Serum Creatinine level was 50 micromol/L.

(a) Calculate a loading dose of procainamide to achieve a plasma concentration of 4 mg/L in this patient.

(b) Calculate the renal clearance (mL/min) of procainamide in this patient.

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(c) Calculate the total clearance (L/h) of procainamide in this patient.

(d) Recommend a suitable infusion rate (mg/h) to maintain a Steady State plasma concentration of 4 mg/L.

(e) Once the infusion is stopped, how long will it take for 80% of the procainamide to be eliminated from the body.

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Question 3. The following graph compares the plasma concentration (Cp, arbitrary units) of a drug with the % of maximum pharmacological response.

(a) Discuss (using diagrams if required) the relationship between the plasma concentration and the pharmacological response in each of the 3 regions indicated on the diagram.

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Question 3 (b) Do you consider that doubling the dose administered will lead to a significant increase in the effectiveness of the drug. Explain your answer.

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Question 4.a Outline the factors (physicochemical, pharmaceutical and physiological) that may influence the elimination pharmacokinetics of a drug.

b. From the factors outlined above, choose up to five that may be a cause of nonlinear pharmacokinetics during drug elimination. Describe, with examples if possible, why your choices can lead to non-linear pharmacokinetics.

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Question 5. Drug Polarity of non-ionised form pKa Clearance (L/h) Fraction excreted unchanged Fraction unbound in plasma Vd (L)

A Non-polar N/A 21 <0.01 0.008 245

B Non-polar 9 (weak base) 10 0.14 0.9 210

C Polar 3 (weak acid) 17 0.27 0.1 25

Consider the properties of the three drugs (A, B and C) in the table above. Indicate the drug or drugs for which each of the statements is most applicable. Give the reason for your answer. (N.B. 1 mark for the correct drug, 3 marks for the correct reason) (a) This drug has the highest hepatic clearance of those listed.

(b) Forced diuresis is most likely to be of value for this drug in case of overdose.

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Question 5 (continued) (c) The renal clearance of this drug is sensitive to changes in urine pH.

(d) After an i.v. bolus, 30% remains in the body at 24 hours

(e) Following a constant rate infusion of 10 mg/h, this drug is expected to reach the highest plasma concentration at 8 hours

(f) At the end of the infusion (above) this drug will remain in the body for the shortest time.

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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- .t + B.exp-

.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

Half-life and elimination rate constant k = Cl Vd ln2 k

= - ln(Cp2/Cp1) t2 t1

Physiological determinants of clearance and volume of distribution CL Hepatic clearance CLHb Renal clearance CLR Volume of distribution = fu.GFR + QR.fu.CLI (1-FR) QR + fu.CLI = QH = Dose/AUC

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Pharmacodynamic response

Accumulation Index

Oral dosing equations Loading Dose LD = Vd Cp F

Incremental Loading Dose

Vd (Cp desired Cp initial) F

Average steady-state = plasma concentration (Cpssave) Cpssmax =

F Dose/ Cl

(Dose) (F) (Vd) (1-e-k )

Cpssmin

(Dose) (F) x e-k (Vd) (1-e-k )

Creatinine Clearance (CrCl)

CrCl (mL/min)

(140-Age) x LBW (kg) xF Serum Creatinine (micromol/L)

F= 1.23 (males) or 1.04 (females)

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Bioavailability

F =

(AUC)oral x Dose iv (AUC)iv x Dose oral

Non-linear Equations

(F) (Dose/ )

(Vm) (Cpss ave) Km + Cpss ave

Cpssave

(Km) [(F) (Dose/ )] Vm - (F) (Dose/ )

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