ENZYME INHIBITIONName: __________________ SS # (optional): ___________________ PHA 5127 Final Exam KEY Fall 2002 On my honor, I have neither given nor received unauthorized aid in doing this assignment. Name Question/Points 1. _______ /12 pts 2. _______ /8 pts 3. _______ /12 pts 4. _______ /27 pts 5. _______ /20 pts 6. _______ /15 pts 7. _______ /20 pts 8. _______ /25 pts 9. _______ /15 pts 10. _______ /6 pts 11. ___5__ /5 Bonus pts TOTAL ______/160 (out 165 possible) 1Name: __________________ SS # (optional): ___________________ 1.) Mark the following statements as True or False (12 points) T F Increasing the dosing interval (τ) of an oral dosing regimen will cause the fluctuation to increase. T F If a patient's plasma protein binding is decreasing for a certain drug so will it's volume of distribution (Assume no other changes). T F The absorption rate constant (ka) is always larger than the elimination rate constant (ke). T F For a drug which behaves like a two compartment body model drug, Vdss is larger than Vdarea.(also called Vdβ) T F The maximum value of renal clearance is that of the glomerula filtration rate. T F Loading doses are more relevant for drugs with long half-lives. 2Name: __________________ SS # (optional): ___________________ 2.) Which graph(s) best depicts a one-compartment body model drug after iv. administration? (8 points) A B Ln(Cp)TimeLn(Cp)TimeC D (Cp)Time Ln(Cp)Time Answer(s): __A__________________________________ 3Name: __________________ SS # (optional): ___________________ 3.) The male patient Whoami is not feeling well. His doctor wants him to take 200 mg of the Drug Yaningho given orally as a tablet. There are two different formulations of the tablet available which differ in the rate with which the tablets disintegrate. Pharmacokinetic studies have shown that the corresponding ka of tablet A is 3.0 h-1 while that of tablet B is 0.01 h-1. Both tablets contain the same amount of Yaningho. Yaningho shows a ke value of 0.3 h-1 after iv bolus administration of the drug. Mark whether the following statements are true or false (12 points) T F Tmax after administration of tablet A will be shorter (smaller) than tmax observed after administration of tablet B T F Cmax after administration of tablet A will be somewhat lower than Cmax observed after iv bolus administration of the same dose T F Cmax after administration of tablet B will be lower than Cmax observed after iv bolus administration of the same dose T F The AUC observed after administration of tablet B will be smaller than that observed after administration of tablet A (assume that drug from both tablets is fully absorbed) T F The correct ke value of Yaningho can be obtained from the terminal phase of the concentration time profile observed after tablet A was administered. T F The correct ke value of Yaningho can be obtained from the terminal phase of the concentration time profile observed after tablet B was administered. 4Name: __________________ SS # (optional): ___________________ 4.) A 14 year old male with history of asthma, patient BG (52 kg) was presented to the hospital in status asthmaticus. On admission the patient’s theophylline levels were not detectable (0 mg/L). The expected therapeutic range is 5-15 mg/L and the desired peak plasma concentration is 12 mg/L. He is given aminophylline as a 400 mg intravenous loading dose over 30 minutes followed by 200 mg intravenous over 30 minutes every 6 hours as maintenance dose (Remember aminophylline is a salt of theophylline and contains 80% theophylline equivalent). The expected pharmacokinetic parameters are a volume of distribution of 26 L and a half-life of 4.5 hours. This information was obtained from published literature for patients similar to BG. (27 points) A. What concentration of theophylline do you expect 4 hours after the stop of the loading dose infusion? LVd 26= ht 5.421= 121154.05.4693.0693.0−=== hhtke hLLhVdkCLe/426154.01=⋅=⋅=− ()()()4154.05.0154.015.0/48.040014⋅−⋅−⋅−⋅−⋅−⋅⋅⋅=⋅−⋅⋅= eehhLmgeeTCLDosehCtkTkee LmgLmg /4.654.0074.0/160=⋅⋅= 5Name: __________________ SS # (optional): ___________________ 4.) continued B. Predict the steady-state peak concentration (1 hour after the stop of the infusion) for the maintenance regimen . ()()()()1154.06154.05.0154.0max,115.0/48.020011⋅−⋅−⋅−⋅−⋅−⋅−⋅−−⋅⋅⋅=⋅−−⋅⋅= eeehhLmgeeeTCLDoseCtkkTksseeeτ LmgLmg /5.8857.06.0074.0/80 =⋅⋅= C. Predict the steady-state trough concentration (directly before the next infusion) for this regimen. ()TksssseeCC−⋅−⋅=τmax,min, ()()()()LmgLmgeehhLmgeeTCLDoseCeekTkss/87.96.0074.0/80115.0/48.0200116154.05.0154.0max,=⋅=−−⋅⋅⋅=−−⋅⋅=⋅−⋅−⋅−⋅−τ ()()LmgeLmgeCCTke/23.4/87.95.06154.0maxmin=⋅=⋅=−⋅−−⋅−τ 6Name: __________________ SS # (optional): ___________________ 5.) The same dose of Alprazolam was given either alone or with ketocozanole. Explain what is going on. (20 points) ENZYME INHIBITION 7Name: __________________ SS # (optional): ___________________ 6.) The following concentration time profiles were observed after multiple short-term infusions over six hours at steady state of a drug. The two curves differ in one of the input parameters (ko, CL, Vd). (AUC represents the AUC observed during one dosing interval) (15 points) Situation 1 2Situatio1 2Ko [mg/ h] 200 200 0 Peak ss 1.5 1.9ta u [h] 4 4 T rough ss 0.8 0.5n 4 4 C ss (mg/L) 1.1 1.1T [h] 1 1 Fluct [%] 48.3 73.3Ke [1/h] 0.22 0.44 t1/ 2 (h) 3.2 1.6Vd [L] 20 10 AUC (mg*h/L) 45.5 45.5CL (L/h)4.44.405101520250102030n Identify the input parameter that differs. 121217.02.3693.0693.0−=== hhtke LhhLkCLVde3.20217.0/4.41===− ⇒ Vd differs Explain your reasoning in one or two sentences. same AUC: CLDoseAUC = ⇒ same CL, same Dose different t1/2: ekt693.021= ⇒ different ke different Vd: ekCLVd = 8Name: __________________ SS # (optional): ___________________ 7.) Consider the following equation. (20 points) tkτkeee)e(11VolumeDoseCp•−•−•−•= a) What does this equation describe? plasma concentration after multiple IV bolus injections b) What do the blocked parts of the equation represent?