DIVISION OFHEALTH SCIENCES

Pharmacokinetics & Biopharmaceutics 201
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DIVISION OF
–HEALTH SCIENCES–
SCHOOL OF –PHARMACY AND MEDICAL SCIENCES–

PHARMACOKINETICS AND BIOPHARMACEUTICS 201

Student Name: ____________________________________ Student ID: _____________________________

Question Value Mark
1 34
2 15
3 27
4 24
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Question 1
The following plasma concentrations (mg/L) relate to a bioavailability study of a new
antibiotic, Zapagerm. The antibiotic has been formulated as a 1000 mg intravenous
injection and as a 1000 mg oral tablet.
Time (h) i.v. (mg/L) oral (mg/L)
1 27.0 1.8
1.5 20.0 2.2
2 14.4 2.6
3 8.0 2.9
4.5 3.2 3.0
6 1.25 2.5
8 Below LOQ 2.0
Preliminary studies have determined that the fraction excreted unchanged (fe) = 1 and
that the fraction unbound (fu) = 1.
(a) Plot the data on the graph paper provided (5 marks)
(b) Determine the equation that describes the plasma concentration (C) following:
i the intravenous dose (3 marks)
ii the oral dose (5 marks)
(c) Calculate the Volume of Distribution of Zapagerm (3 marks)
(d) Calculate the Bioavailability of the oral tablet (4 marks)
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(e) From what you know about the drug, discuss the factors that are likely to be
the major determinants of its bioavailability. (4 marks)
(f) By appropriate calculations determine the factors that are likely to be
important in the renal clearance of this drug. (4 marks)
A follow up study was conducted using a 3000 mg dose. It was found that the
AUC of the 3000 mg intravenous formulation increased by 450% (i.e. 4.5x)
compared to the 1000 mg i.v. dose, whereas the AUC of the 3000 mg oral dose
increased by 300% (i.e. 3x) compared to the 1000 mg oral dose.
(g) Using your knowledge of pharmacokinetics and the answers above, discuss the
likely mechanism/s that would account for this observation.
(6 marks)
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Question 2
A patient comes into the pharmacy with a prescription for E-mycin (erythromycin)
400mg qid for 14 days. When dispensing her prescription you notice that she is
currently taking digoxin and an oral contraceptive pill – Levlen ED. Her history
shows that she has been on both medications for at least 3 months. Discuss the
potential drug interactions that may occur, considering the effect of the new antibiotic
medication on the oral absorption and bioavailability of digoxin and the pill. Detail
the mechanisms that cause these interactions and recommend what action should be
taken. (15 marks)
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Question 3
Fluoroquinoline antibiotics are effective against a range of gram positive and gram
negative bacteria causing infections in humans. Their effect is concentrationdependent; in other words, it is most efficacious when high initial maximum
concentrations are achieved following doses administered at regular intervals. The
following data was available on the pharmacokinetics of a selected group from a wide
range within the fluoroquinoline class of compounds. Absorption of all three is quite
rapid.
Table 1: Pharmacokinetic parameters for a series of fluoroquinoline antibiotics
Drug (Dose in mg) Cmax
(μg/mL)
AUC
(μg.h/mL)
Half-life
(h)
Foral CLR
(mL/min)
MIC90
Ciprofloxacin (250) 1.5 5.8 5.4 0.70 266 0.1
Gatifloxacin (400) 3.4 30 10 0.96 150 0.1
Moxifloxacin (400) 4.3 39 12 0.90 30 0.1
(a) Determine the most appropriate dosage regimen for ciprofloxacin with the
following assumptions:

(iii) that minimum concentrations of approximately 10% to 20% of the
maximum concentration are reasonable
(12 marks)
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(b) For which of the above three drugs is a decrease in renal clearance likely to have
the least impact on the oral dosing regimen? Explain.
(5 marks)
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(c) Do you believe that steady-state concentrations of moxifloxacin will have been
achieved after oral doses have been administered for seven days. Justify your
answer.
(5 marks)
(d) If the patient began taking another drug known to interfere with the metabolism
of fluoroquinoline antibiotics, for which of the three antibiotics in Table 1 is a
metabolic interaction likely to have the most impact on its dosage regimen?
Briefly explain.
(5 marks)
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Question 4
Consider the following schematic:
In the space provided, sketch the drug and the metabolite concentration-time profiles
that you would expect following a single oral dose in each of the following situations.
Under each sketch, write a few lines describing the key features of the profile.
(a) Ke is much smaller than Km, and Ka is much larger than Km. (6 marks)
Ke = Kf + Ko
Note from Dr Foster: I teach this material using clearances and half-lives. The key here is to recognise
that a rate constant is inversly proportional to a half-life: a smaller rate constant results in a longer
half-life.
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(b) Km is much smaller than Ke, and Ka is much larger than Ke. (6 marks)
(c) Ka is much smaller than either Ke or Km. Km is larger than Ke (6 marks)
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(d) Discuss whether the value of Km needs be taken into account when designing a
dosing and therapeutic drug monitoring regimen for a patient.
(6 marks)
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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

Physiological determinants of clearance and volume of distribution
CL = Dose/AUC
Hepatic clearance
CLHb = QH
Renal clearance
CLR = fu.GFR + QQRR+ f .fuu.CL .CLII (1-FR)
Volume of distribution
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Pharmacodynamic response
Accumulation Index
Oral dosing equations

Average steady-state = F Dose/

Cpssmax = (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) x F
Serum Creatinine (micromol/L)
F= 1.23 (males) or 1.04 (females)
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Bioavailability

Non-linear Equations
(F) (Dose/) = (Vm) (Cpss ave)
Km + Cpss ave
Cpssave = (Km) [(F) (Dose/)]
Vm – (F) (Dose/)

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