SchoolPMBSubject Area &Catalogue numberPHAR 2006Paper1Course NamePharmacokinetics and Biopharmaceutics 201 Student IDGiven Name/sSurnameIf you are required to use acalculator, please note the makeand model hereMake:Model Writing Time: 2 hrs QuestionMarks134224321421 Instructions to Candidates:Answer all questions.Show all calculations and assumptions in the answer book.Write your name and Student ID number on all loose graph papers.Equation Sheet is attached.Semi log graph paper is provided.Permitted Materials• Non-programmable calculatorDO NOT COMMENCE WRITING UNTIL INSTRUCTED TO DO SOPage 1 of 14Question 1A 40 mg dose of the drug Nohopealol was given to a healthy volunteer. The amount excretedunchanged in urine during the study (7 h) was 3 mg. It is known that the drug has a fu of 0.05and a blood to plasma ratio of 0.9. The following data was obtained from plasma samplescollected: Time(h)0.250.511.522.533.54567PlasmaConcentration(µg/L)4703201538046302014105.93.42 (a) Plot the concentration-time profile of Nohopealol on the semi-log graph paper provided.(5 marks)(b) Derive the equation that describes the plasma-concentration profile. (5 marks)(c) Calculate the plasma clearance. (4 marks)(d) Calculate the initial Volume of Distribution (2 marks)(e) Calculate the terminal Volume of Distribution (2 marks)Page 2 of 14(f) Estimate the hepatic extraction ratio (4 marks)Discuss whether an increase in fu will significantly affect the following parameters. Where aparameter is likely to be affected indicate whether this will be an increase or decrease in thevalue of the parameter.(g) Plasma Clearance (3 marks)(h) Volume of Distribution (3 marks)(i) Bioavailability following administration of an oral dose (3 marks)(j) Bioavailability following administration of a suppository (3 marks)Page 3 of 14Question 2The 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 aweak acid with a pKa of about 4.3• Fraction unbound 0.8• Volume of distribution 70 L• Clearance 2 L/hour• Renal clearance 1.98 L/hour• Absolute oral bioavailability of a compressed tablet• Desired plasma level0.20.1 mg/L • Molecular weight 198 g/mole• Solubility in waterof unionised species 1 in 500Provide answers to the following questions in the spaces provided. Your answers will bemarked 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 oralbioavailability and those factors that are unlikely to be involved. (8 marks)Page 4 of 14(b) What strategies might you employ to improve the bioavailability of CDR1? (8 marks)(c) Explain whether administration of sodium bicarbonate is likely to be beneficial in thecase of an overdose of CDR1 (use calculations to support your conclusions).(8 marks)Page 5 of 14Question 3Shortoderone is a new anti-arrhythmic drug structurally related to amiodarone. It is indicatedfor the treatment of tachyarrhythmia. It has the following pharmacokinetic properties for the“average” human:• Fraction unbound 1%• Volume of distribution 9 L/kg• Clearance 2.0 ml/min/kg• Fe < 0.02• Oral bioavailability 50%• Oral tablets (may be halved) 200 mg and 400 mgShortoderone has been shown to be ineffective at steady-state blood concentrations below 1mg/L and to cause the serious toxicities (neuropathy, bradycardia, neurotoxicity) at steadystate concentrations above 3.6 mg/L. Current guidelines recommend a Css,ave of 2 mg/L.Mr Heart (70 kg) has been admitted to the cardiac ward and is to be administeredShrotoderone to control his serious ventricular tachyarrhythmia.Showing your calculations, answer the following questions:(a) What IV loading dose would you use to rapidly control Mr Heart’s arrythmia?(2 marks)(b) To prevent acute side effects, this loading dose is to be administered at a rate of2500 mg/hr in a total volume of 50 mL of fluid. At what flow rate would the infusionpump need to be set at?(3 marks)Page 6 of 14(c) After the loading dose, Mr Heart is to be started on a continuous IV infusion. What doserate would you use? (2 marks)(d) Two days later Mr Heart is transferred to oral administration of Shortoderone only. Thedosing regimen he has been prescribed is 2 x 400 mg tablets once a day.(i) What is the Css,max of this regimen?(2 marks)(ii) What is the Css,min of this regimen?(1 mark)(iii) What would be the maximum inter-dosing interval that could be employed for MrHeart with this drug?(2 marks)Page 7 of 14(iv) Discuss whether or not administering the drug once daily (as prescribed) is preferableto administering the drug at the maximum dose interval that you calculated in d(iii).(3 marks)(e) If Mr Heart was suffering from mildly reduced cardiac output, what effect would this haveon the steady-state concentrations of Shortoderone? Provide the reasons for your answer.(3 marks)(f) Amiodarone has a volume of distribution of 60 L/kg while its clearance is very similar toShortoderone. Comment on the advantages that this might afford Shortoderone.(3 marks)Page 8 of 14Question 4Below is part a plasma concentration- time profile obtained for drug X and one of itsmetabolites X-4-G. Drug X was administered as an intravenous infusion to an adult male(lean body weight = 95 kg) for 180 min. After 180 minutes the infusion was switched off.Drug X has an elimination half life of 30 min and the Vd is 80 L. It is completely metabolised(fe = 0) to a number of metabolites. One of the metabolites (X-4-G) is active. Its potency ismuch greater than that of the parent drug and most of the pharmacological and toxicologicaleffects are thought to reside with X-4-G. All other metabolites are inert.The Vd of X-4-G is 20 L and its fe = 1. Neither drug X nor X-4-G bind to plasma proteins (fu =1).(a) From the information provided suggest the most likely infusion rate. (6 Marks)Page 9 of 14(b) Complete the sketch of drug X ‘s plasma concentration-time profile from 0 to 240mins. Use the graph provided in the question to do this. Highlight any key features ofthe profile including time to SS and CPss. Show any calculations required to justifyyour answer in the space below.(4 marks)(c) Complete the sketch of X-4-G ‘s plasma concentration-time profile from 0 to 240mins. Use the graph provided in the question to do this. Highlight any key features ofthe profile including time to SS and CPss. Show any calculations required to justifyyour answer in the space below.(4 marks)(d) Briefly discuss why the Vd and route of clearance of the metabolite is different fromthe parent drug. (2 marks)Page 10 of 14(e) If the renal function of the patient was to fall significantly indicate whether this wouldaffect the clearance of drug X. Following this, discuss whether any change in the dosewould be needed to maintain the same therapeutic effect. (5 marks)End of Examination PaperPage 11 of 14Equations 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-α.t + B.exp-β.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 doseC = .. kaDoseF [ – .tk – expexp – .tka ]– kkaVd ).(Half-life and elimination rate constantk = ClVdt½ = ln2kk = – ln(Cp2/Cp1)t2 – t1Physiological determinants of clearance and volume of distribution CL=Dose. F/AUCHepatic clearance⎞CLHb=QH⎛⎜f .CLu int ⎟⎝ Q + f .CL H u int ⎠Renal clearanceCLR =⎛⎜⎝⎞⎟⎠fu.GFR +QR.fu.CLIQR + fu.CLI (1-FR)Page 12 of 14Volume of distribution TTfuPPharmacodynamic response fu+= VVVdnnnCECCEE+=50max .Accumulation Index⋅- τ–=A kAssexp111max,maxOral dosing equationsLoading Dose = Vd CpLD FIncremental = Vd (Cp desired – Cp initial)Loading Dose FAverage steady-state = F Dose/τplasma concentration Cl(Cpssave) Cpssmax =(Dose) (F)(Vd) (1-e-kτ ) Cpssmin =(Dose) (F) x e-kτ(Vd) (1-e-kτ) 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 14Page 14 of 14BioavailabilityF = (AUC)oral x Dose iv(AUC)iv x Dose oralNon-linear Equations(F) (Dose/τ) = (Vm) (Cpss ave)Km + Cpss ave Cpssave=(Km) [(F) (Dose/τ)]Vm – (F) (Dose/τ)
