Plasma concentrations during an intravenous infusion

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UNIVERSITY OF SOUTH AUSTRALIA
SCHOOL OF PHARMACEUTICAL, MOLECULAR AND BIOMEDICAL
SCIENCES
PHARMACOKINETICS AND BIOPHARMACEUTICS
TIME: 2 HOURS
General Instructions to Candidates Name _____________________
Student Number _____________
Hello and welcome to the exam. Please read the following instructions.
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.
The mark allocated to each question is shown in the table below.
For multiple choice questions, only one answer is correct.
Please ensure that your answers are in the correct units.
For examiners use only

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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
Physiological determinants of clearance and volume of distribution
Hepatic clearance
Renal clearance
Volume of distribution
Pharmacodynamic response
Accumulation Index
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1. Serenel® is a new amphetamine-like compound being developed for use in the
treatment of attention-deficit hyperactivity disorders and related conditions. The drug
is a weak base with a pKa of 8.8. In a first-time-in-man Phase 1 study, the drug was
administered as a single intravenous bolus (50mg) and a single oral dose (50mg) to
healthy adult males (18-30 years of age). The oral dose consisted of a dry powder
placed inside a gelatin capsule. The following mean plasma concentration-time data
were obtained.

Urine was collected for 24 hours after intravenous dosing and was found to contain
40 mg of unchanged drug and 8mg of a metabolite.
(a) Plot the data, and
(b) Calculate the following pharmacokinetic parameters
(i) Elimination half-life
(ii) Volume of distribution (referenced to plasma)
(iii) Clearance (referenced to plasma)
(iv) Renal Clearance (referenced to plasma) after the
intravenous dose (note units)
hours
L
L/h
mL/min
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Question 1 (continued)
(c) Determine the equation that describes the plasma concentration versus time
profile of the drug after oral administration. Give your answer in the following
format:
C = A(e-x.t – e-y.t)
(d) Calculate the absolute bioavailability of the drug after administration of the oral
capsule
(e) Given that the fraction of drug unbound in plasma is 0.23, determine the likely
mechanisms involved in the renal excretion of this drug.
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(f) On the basis of your answers to the above questions and the known
physicochemical properties of the drug, provide some predictions about how the
following factors might alter the pharmacokinetics of the drug (including the likely
effect on clearance, volume of distribution and half-life.
(i) An increase in urine pH
(ii) Induction of hepatic enzymes involved in the oxidation of the drug
(iii) Displacement of the drug from plasma binding sites
(iv) Coadministration of the drug cimetidine, which is an inhibitor of hepatic drug
metabolism and is able to inhibit the renal tubular secretion of organic cations.
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2. Mexilitine is an antiarrhythmic agent with the following pharmacokinetic
properties:
Clearance = 5.02 mL/min/kg
Volume of Distribution = 3.46 L/kg
(a) If mexilitine was given by repeated intravenous bolus doses, of 200mg every 8
hours, to a 60-kg patient calculate the plasma concentration:
(i) just after the first dose (Cmax)
mg/L
(ii) at the end of the first dose interval (Cmin)
mg/L
(iii) just after a dose at steady state (Cmax,ss)
mg/L
(iv) just before a dose at steady state (Cmin,ss)
mg/L
(b) If mexilitine was infused at a constant rate of 25mg per hour, what would be the
plasma levels after
(i) 8 hours
(ii) 16 hours
(iii) at steady state
mg/L
mg/L
mg/L
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(c) If mexilitine was given as a bolus dose of 400mg and then infused continuously at
a rate of 20mg per hour, how would the plasma concentration versus time curve
appear (provide a sketch and show your calculations below).
(d) For what reason would a drug be administered as a fast infusion rate for a short
time followed by a slower infusion rate thereafter, as in the example given in part (b)
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3. Describe the factors that can vary the rate of gastric emptying. Explain how these
factors can influence the oral absorption of a drug (give examples where possible).
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4. The following pharmacokinetic parameters and properties have been elucidated for
a drug (CDR I) being developed for the treatment of dementia of the Alzheimer’s
type. The drug is a weak acid with a pKa of about 4.3
• Volume of distribution 70 L
• Clearance 2 L/hour
• Renal clearance 1.98 L/hour
• Absolute oral bioavailability
of a compressed tablet 0.2
• Desired plasma level 0.1 mg/L
• Molecular weight 198 g/mole
• Solubility in water
of unionised species 1 in 500
Provide answers to the following questions in the spaces provided. Your answers
will be marked according to clarity and relevance as well as accuracy of content.
(a) Briefly explain what factors are likely to contribute to this drug having a poor oral
bioavailability and those factors that are unlikely to be involved.
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(b) In evaluating whether this drug would be a suitable candidate for transdermal drug
delivery, what factors would you consider and on the basis of the information
provided, what would be your assessment for CDR I?
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5. The following questions will draw on your knowledge and understanding of the
areas of metabolite kinetics, non-linear pharmacokinetics and pharmacological
response. Please answer the questions clearly and precisely.
Alprenolol is a beta-blocker which decreases the normal increase in heart rate that
occurs in response to exercise. It does this by blocking the beta adrenoreceptors in the
heart. Alprenolol is a drug with good absorption but low bioavailability (F = 0.2) due
to extensive first-pass hepatic metabolism. Its main metabolite is pharmacologically
active and also exhibits beta-blocker activity similar to alprenolol. The half-life of
alprenolol is about 1-2 hours.
(a) The following figure shows the effect of alprenolol on exercise heart rate in
humans. The graph suggests that the drug is more potent after oral administration that
after intravenous dosing. Provide a possible explanation for these findings.
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Question 5 (continued)
(b) The following graph show that with increasing dose of oral alprenolol (50, 100
and 200mg) there is a greater than proportional increase in plasma concentration (left
panel). Despite this, the effects of the three doses on exercise heart rate are quite
similar.
Provide brief possible explanations for:
(i) the non-linear pharmacokinetics of alprenolol (with increasing dose)
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Question 5 (continued)
(ii) the small increase in drug effect despite the large increase in plasma concentration
(with increasing dose)
(iii) why the effects of the drug have not disappeared by 7 hours (after dosing) even
though the plasma levels have returned to zero

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