Pharmacokinetics & Biopharmaceutics 201Page 1 of 13DIVISION OF–HEALTH SCIENCES–SCHOOL OF –PHARMACY AND MEDICAL SCIENCES– Subject Area:PharmacyCatalogue Number: PHARMACOKINETICS AND BIOPHARMACEUTICS 201 Examination Day: TuesdayExamination Time: 18.30Length of Exam: 2 h Student Name: ____________________________________ Student ID: _____________________________ Instructions to CandidatesAnswer all questions in the spaces provided.Calculators may be usedGraph 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 Mark1 342 153 274 24Page 2 of 13Question 1The following plasma concentrations (mg/L) relate to a bioavailability study of a newantibiotic, Zapagerm. The antibiotic has been formulated as a 1000 mg intravenousinjection and as a 1000 mg oral tablet.Time (h) i.v. (mg/L) oral (mg/L)1 27.0 1.81.5 20.0 2.22 14.4 2.63 8.0 2.94.5 3.2 3.06 1.25 2.58 Below LOQ 2.0Preliminary studies have determined that the fraction excreted unchanged (fe) = 1 andthat 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)Page 3 of 13(e) From what you know about the drug, discuss the factors that are likely to bethe major determinants of its bioavailability. (4 marks)(f) By appropriate calculations determine the factors that are likely to beimportant in the renal clearance of this drug. (4 marks)A follow up study was conducted using a 3000 mg dose. It was found that theAUC 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 doseincreased by 300% (i.e. 3x) compared to the 1000 mg oral dose.(g) Using your knowledge of pharmacokinetics and the answers above, discuss thelikely mechanism/s that would account for this observation.(6 marks)Page 4 of 13Question 2A 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 iscurrently taking digoxin and an oral contraceptive pill – Levlen ED. Her historyshows that she has been on both medications for at least 3 months. Discuss thepotential drug interactions that may occur, considering the effect of the new antibioticmedication on the oral absorption and bioavailability of digoxin and the pill. Detailthe mechanisms that cause these interactions and recommend what action should betaken. (15 marks)Page 5 of 13Question 3Fluoroquinoline antibiotics are effective against a range of gram positive and gramnegative bacteria causing infections in humans. Their effect is concentrationdependent; in other words, it is most efficacious when high initial maximumconcentrations are achieved following doses administered at regular intervals. Thefollowing data was available on the pharmacokinetics of a selected group from a widerange within the fluoroquinoline class of compounds. Absorption of all three is quiterapid.Table 1: Pharmacokinetic parameters for a series of fluoroquinoline antibioticsDrug (Dose in mg) Cmax(μg/mL)AUC(μg.h/mL)Half-life(h)Foral CLR(mL/min)MIC90Ciprofloxacin (250) 1.5 5.8 5.4 0.70 266 0.1Gatifloxacin (400) 3.4 30 10 0.96 150 0.1Moxifloxacin (400) 4.3 39 12 0.90 30 0.1(a) Determine the most appropriate dosage regimen for ciprofloxacin with thefollowing assumptions: (i)that maximum concentrations of approximately 10-times the MIC90 arerequired during administrationthat a full course of tablets is usually administered for up to 7 days(ii) (iii) that minimum concentrations of approximately 10% to 20% of themaximum concentration are reasonable(12 marks)Page 6 of 13(b) For which of the above three drugs is a decrease in renal clearance likely to havethe least impact on the oral dosing regimen? Explain.(5 marks)Page 7 of 13(c) Do you believe that steady-state concentrations of moxifloxacin will have beenachieved after oral doses have been administered for seven days. Justify youranswer.(5 marks)(d) If the patient began taking another drug known to interfere with the metabolismof fluoroquinoline antibiotics, for which of the three antibiotics in Table 1 is ametabolic interaction likely to have the most impact on its dosage regimen?Briefly explain.(5 marks)Page 8 of 13Question 4Consider the following schematic:In the space provided, sketch the drug and the metabolite concentration-time profilesthat 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 + KoNote from Dr Foster: I teach this material using clearances and half-lives. The key here is to recognisethat a rate constant is inversly proportional to a half-life: a smaller rate constant results in a longerhalf-life.Page 9 of 13(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)Page 10 of 13(d) Discuss whether the value of Km needs be taken into account when designing adosing and therapeutic drug monitoring regimen for a patient.(6 marks)Page 11 of 13Equations and physiological valuesGlomerular filtration rate = 120 mL/minHepatic blood flow = 1.5 L/minRenal blood flow = 1.2 L/minCardiac output = 5 L/minHaematocrit = 0.5Plasma concentrations after an intravenous bolus– monoexponential C = C(0).exp-k.t– biexponential C = A.exp-.t + B.exp-.tPlasma concentrations during an intravenous infusion (monoexponential only)C = (Ro/CL).(1-exp(-k.t))where Ro is the zero-order infusion ratePlasma concentrations after an extravascular doseHalf-life and elimination rate constant k= ClVd t= ln2k k= – ln(Cp2/Cp1)t2 – t1 Physiological determinants of clearance and volume of distributionCL = Dose/AUCHepatic clearanceCLHb = QHRenal clearanceCLR = fu.GFR + QQRR+ f .fuu.CL .CLII (1-FR)Volume of distributionPage 12 of 13Pharmacodynamic responseAccumulation IndexOral dosing equations Loading Dose= Vd CpLDF Incremental= Vd (Cp desired – Cp initial)Loading DoseF 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 FSerum Creatinine (micromol/L)F= 1.23 (males) or 1.04 (females)Page 13 of 13Bioavailability F =(AUC)oral x Dose iv(AUC)iv x Dose oral Non-linear Equations(F) (Dose/) = (Vm) (Cpss ave)Km + Cpss aveCpssave = (Km) [(F) (Dose/)]Vm – (F) (Dose/)
