Pharmacokinetics & Biopharmaceutics 201

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DIVISION OF

–HEALTH SCIENCES–

SCHOOL OF –PHARMACY AND MEDICAL SCIENCES–

Subject Area: | Pharmacy | Catalogue Number: |

PHARMACOKINETICS AND BIOPHARMACEUTICS 201

Examination Day: Tuesday | |

Examination Time: 18.30 | 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 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:

(i) | that maximum concentrations of approximately 10-times the MIC90 are required during administration that a full course of tablets is usually administered for up to 7 days |

(ii) |

(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

k | = Cl Vd |

t | = ln2 k |

k | = – ln(Cp2/Cp1) t2 – t1 |

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

Loading Dose | = Vd Cp |

LD | F |

Incremental | = Vd (Cp desired – Cp initial) |

Loading Dose | F |

Average steady-state = F Dose/

plasma concentration (Cpssave) | Cl |

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

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/)