PHA 5128 Final Exam Spring 2004 Version A. On my honor, I have neither given nor received unauthorized aid in doing this assignment.

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1 PHA 5128 Final Exam Spring 2004 Version A On my honor, I have neither given nor received unauthorized aid in doing this assignment. Name There are 18 questions. Total /120 pts Final

2 1. T.P., a 66-year-old, 72 kg male (SrCr 1.6mg/dL), has been taking 0.25mg of digoxin tablets orally for his CHF, and at 9.00am on the day of admission, a digoxin plasma concentration of 1.1µg/L was measured. He was continued on his outpatient maintenance dose. On the third day, just before his morning dose (two doses of digoxin have been administered each day at 9.00am), a second digoxin sample was obtained. Using the expected pharmacokinetic parameters, calculate L.P. s digoxin concentration on the morning of the third day. (8 pts.) A. 0.6 µg/l B. 1.0 µg/l C. 1.3 µg/l D. 1.6 µg/l E. 1.9 µg/l Key : C ( ) 72 CL Cr 46.25mL / min CL mL / min 3.9L / h 93.6L / day Vd L 417L k e CL Vd days 1 C min( sum ) 1.1 e C measured days e k e t F D + Vd k t [ e e t 1 k + e e 2 ] days days [ e + e ] µg / L [ ] Final

3 2. S. J., a 70 kg female patient was given 60 mg gentamicin over 30 minutes (i.v.) from 8:30 to 9:00 am. The following two serum levels were measured: 6.5 µg/ml at 9:30 am and 1.2 µg/ml at 4:00 pm. Calculate his peak concentration at 9:00 am. (6 pts.) A. 7.0 μg/ml B. 7.4 μg/ml C. 7.8 μg/ml D. 8.2 μg/ml E. 8.6 μg/ml Key: B The elimination rate constant k is k 6.5 ln h 1 The peak concentration at 9:00 am is C max e μg / ml Final

4 3. M.F., a 28-year-old, 75 kg male, is receiving 100 mg of tobramycin infused IV over 30 minute period q8h. His serum creatinine has increased from 1 mg/dl to 1.8 mg/dl over the past 24 hours. Since his renal function appears to be decreasing, three plasma samples were obtained to monitor serum gentamicin concentrations as follows: just before a dose; one hour after the start of that same dose; and eight hours after the start of that dose (two troughs and one peak level). The serum tobramycin concentrations at these times were 4 mg/l, 8 mg/l, and 5 mg/l, respectively. Calculate the volume of distribution of tobramycin for M.F using the following equation. (6 pts.) Vd 100 k 0.5 k 0.5 ( 1 e ) k 0.5 ( C C e ) max min What should be the values for k (h -1 ), Cmax (mg/l) and Cmin (mg/l) in the above equation? A , 8.3, 5 B , 8, 5 C , 8.3, 4 D , 8, 4 E , 8, 5 Key: C 8 ln k 0.067h max C e 8 mg/l Cmin should be the pre-dose concentration 4 mg/l. Final

5 4. Show how an increase in tissue binding will affect the clearance, bioavailability and halflife of a high-extraction drug. (6 pts.) A. Clearance is decreased, bioavailability is not changed, Half-life is increased B. Clearance is decreased, bioavailability is not changed, Half-life is not changed C. Clearance is not changed, bioavailability is not changed, Half-life is not changed D. Clearance is not changed, bioavailability is not changed, Half-life is increased E. Clearance is decreased, bioavailability is increased, Half-life is increased Key: D Vd fu VB + VT fu T Clearance and bioavailability are not changed Half-life is increased due to increase in Vd Final

6 5. V.W., a 15-year-old, 32 kg male, is receiving 250 mg of valproic acid q12h for absence seizures. His steady-state trough concentration was 30 mg/l. Because of inadequate seizure control and the lack of apparent side effects, it is decided to increase the trough concentration to 55 mg/l. What dose will be required to achieve the target trough concentration of 55mg/L if the dosing interval is decreased from q12h to q8h? (8 pts.) A. 120 mg q8h B. 250 mg q8h C. 125 mg q8h D. 80 mg q8h E. 400 mg q8h Key: B Vd 0.14L / kg weight 0.14L / kg 32kg 4. 48L Dose F S 250mg 1 1 C max Cmin + 30mg / L mg / L Vd 4.48L Cp1 85.8mg / L ln ln Cp2 30mg / L 1 k e 0.088h t 12h ke τ Cpss Vd e mg L L e 124.5mg Dose,min 1 55 / ke τ F S e 1 1 e mg q8h ( ) ( ) mg mg Final

7 6. S.V., a 34 y.o. female patient (54 kg, SeCr 1.1 mg/dl) received a 30 mg methotrexate loading dose iv followed by a 30 mg/h infusion over 36 hours. Her levels at 24h and 48h were 12.2 µm and 0.76 µm, respectively. Calculate the anticipated methotrexate level at 60 hours. (8 pts.) A. 0.5 µm B µm C. 0.1 µm D µm E. 0.4 µm Key: D Cp ln Cp t µM ln 0.76 µm h 2 1 k e h t 1 3h 2 t at 0.5 µm: Cp1 12.2µM ln ln Cp 2 0.5µM t 1 k 0.231h e 13.8h t 3h t h h 13.8h 36h 10. 2h ( 60h) 0.5µM e 0. µm Cp 25 k e h t 10h 1 2 Final

8 7. T.K. is a 25 year old 75 kg chronic asthmatic who is hospitalized with severe asthma. She is treated there with aerosol albuterol, but has a poor response. She is then given 350 mg of IV aminophylline over 30 minutes. Thirty minutes after the loading dose was administered (60 minutes from time zero) the theophylline concentration was 10 μg/ml. She has normal liver, kidney, and cardiac function and is afebrile. After the loading dose, T.K. was started on an IV aminophylline of 60mg/h and albuterol nebulization. Eight hours after the first serum level, a second level was 16 μg/ml. Using T.K.'s actual volume of distribution, calculate her expected steady state theophylline concentration for the infusion rate of 40mg/h aminophylline. (8 pts.) A. 10 μg/ml B. 15 μg/ml C. 20 μg/ml D. 25 μg/ml E. 30 μg/ml Key: B Vd D * S C * L (10 16 ) CL ( ) ( ) L / h C μg / ml Final

9 8. A patient (male, 35y, 74 kg) with a subtherapeutic theophylline (3 μg/ml) is admitted to the ICU. Based on average pharmacokinetics parameters (Vd 0.5 L/kg, t 1/2 8 h)), calculated an i.v. bolus loading dose and a maintenance dose (i.v. infusion) to increase the level to 15 μg/ml. (6 pts.) A. 350mg, 50mg/h B. 450mg, 40mg/h C. 450mg, 50mg/h D. 550mg, 40mg/h E. 550mg, 50mg/h Key: C V d L LD (15 3 ) mg CL 37 8 MD mg/h 3.21L / h Final

10 9. Z. T., a 62-year old, 60-kg woman with a serum creatinine of 1 mg/dl, has been started on 500 mg of vancomycin every 8 hours for the treatment of staphylococcal infection. What is the expected trough vancomycin concentrations for her at steady state? (6 pts.) A. 20 mg/l B. 13 mg/dl C. 13 mg/l D. 26 mg/dl E. 26 mg/l Key: C Vd 0.17(62)+0.22(60) L CL Cl cr 0.85 ( )(60 ) ml/min 3.32 L/h 72 1 Ke CL/Vd 3.32/ h -1 S F Dose (1)(1)( 500 ) Vd ( ) Css max k τ e 1 e 26mg / L k τ Css min Css max e 26.0 e 13mg / L Final

11 Key : B 10. Inhibition of P-glycoprotein will result in A. lower cyclosporin bioavailability and lower digoxin levels in the brain B. higher cyclosporin bioavailability and higher digoxin levels in the brain C. higher cyclosporin bioavailability and unchanged digoxin levels in the brain D. unchanged cyclosporin bioavailability and lower digoxin levels in the brain E. lower cyclosporin bioavailability and higher digoxin levels in the brain (6 pts.) Final

12 11. Which of the following statements about the pharmacokinetics (PK) and pharmacodynamics (PD) of midazolam in elderly patients is correct? (6 pts.) A. PK and PD are the same as in young patients B. PK is the same as in young patients, but PD is different C. PD is the same as in young patients, but PK is different D. PK and PD are different in comparison to young patients E. PD is different compared to young patients due to changes in PK Key : B Final

13 12. Which of the following changes goes along with an increased clearance and no change in volume of distribution? (6 pts.) A. increased initial concentration after an i.v. bolus, longer time to steady state B. shorter half-life, higher steady state concentration C. longer time to steady state, shorter half life D. shorter time to steady state, lower steady state concentration E. shorter time to steady state, higher steady state concentration Key : D Final

14 13. A 50 year-old female (5 4, 125 lbs) is admitted to the emergency room with ventricular tachycardia and chest pain consistent with an evolving mycardial infarction. She is given a bolus of lidocaine and started immediately on a lidocaine infusion of 2 mg/min. Routine laboratory analyses reveal a serum creatinine and BUN of 3.0 and 48 mg/100 ml, respectively. Although lidocaine eliminates ventricular tachycardia, frequent hemodynamically significant ventricular ectopy is still present 12 hours later. Procainamide is given first as a loading dose of 17 mg/kg over one hour and then followed by a maintenance infusion of 120 mg/hour. Serum concentrations of procainamide and NAPA at the end of the loading infusion are 7 and 4 mg/l, respectively. Serum concentrations of procainamide one, six, and 24 hours following initiation of maintenance infusion are 7, 8 and 9 mg/l, respectively. Corresponding values for NAPA are 4, 9, and 14 mg/l, respectively. Ventricular ectopy is completely abolished beginning about 30 minutes after the loading infusion was administered and no further arrhythmias are noted. The physician now wants to dose procainamide orally. Make appropriate dose recommendations for use of oral procainamide in this atient. You must show all calculations and clearly state all assumptions. (8 pts.) A mg B. 870 mg C. 550 mg D. 480 mg E. 200 mg Key: C or B weight / kg 125lbs kg CL R 0 F S Cp ss 120mg / h L / h 9mg / L LD F S 17mg / kg 56.75kg Vd L Cp 7mg / L Vd L t h 7h 2 CL 11.33L / h k e t h 7h Final

15 the dosing interval should be equal or less than the half-life Cp1 8mg / L ln Cp ln 2 4mg / L τ 7h τ 6h ke Cpss CL τ 6mg / L 11.33L / h 6h mg Dose mg 550mg F S C if you chose a dosing interval of τ 8h : Cpss CL τ 6mg / L 11.33L / h 8h mg Dose mg 870mg F S B Final

16 14. M.W. is a 33-year-old, 65 kg male with a seizure disorder that has only partially been controlled with 300 mg/day of sodium phenytoin. His plasma phenytoin concentration has been measured twice over the past year and both times it was reported to be 7 mg/l. His Km value is 5 mg/l. Calculate a dose which will achieve a steady-state concentration of 15 mg/l. (6 pts.) A. 800 mg B. 400 mg C. 200 mg D. 250 mg E. 600 mg Key: B Vm F S Dose / τ Cp ( Km + Cpss, ave ) mg / day ( 5mg / L + 7mg / L) ss, ave 7mg / L mg / day 7 Dose Vm Cp ss, ave 473mg / day 15mg / L 1day ( Km + Cp ) F S ( 5mg / L + 15mg / L) ss, ave τ mg 400mg 18.4 Final

17 15. N.S., a 36-year-old, 60 kg female, is to be given carbamazepine orally as an anticonvulsant agent. Calculate a daily dose that will produce an average steady-state plasma concentration of approximately 6 mg/l. (6 pts.) A. 30 mg B. 350 mg C. 700 mg D mg E. 45 mg Key: C CL 0.064L / kg / h weight 0.064L / kg / h 60kg 3.84L / h Cp Dose ss, ave CL τ 6mg / L 3.84L / h 24h F S mg 700mg Final

18 16. E.S., an 8-year-old, 25 kg male, is being treated for a seizure disorder. She has been receiving 100 mg/day of phenobarbital (50 mg BID) for the past 20 days. The phenobarbital serum concentration just before the morning dose on Day 21 (i.e., at the trough of the 40 th and just prior to the 41 st dose) was reported to be 27 mg/l. Calculate the phenobarbital concentration you would have predicted on that day if E.S. has average pharmacokinetic parameters for phenobarbital. (6 pts.) A mg/l B mg/l C mg/l D mg/l E mg/l Key: A CL 0.008L / h / kg weight 0.008L / h / kg 25kg 0.2L / h 4.8L / day Vd 0.7L / kg weight 0.7L / kg 25kg 17. 5L k e CL 0.011h 0.27days Vd 17.5L 0.2L / h 1 1 Dose F S 50mg 1 1 Vd k τ L 2.9mg / L Cp e min e e ke τ ( 1 e ) ( 1 e ) 20.5mg / L Final

19 17. S.K., a 42-year-old, 54 kg woman, received a renal transplant 1.5. years ago. Following transplantation, her serum creatinine stabilized in the range of mg /dl. She has been receiving cyclosporine orally, 125mg BID over the past six months. Cyclosporine concentrations have been µg/l (whole blood HPLC assay). Her last clinic appointment was four weeks ago. Other immunosuppressive medications included prednisone 25 mg/day, azathioprine 50 mg HS. She returned to clinic yesterday complaining of increasing fatigue since her last clinic appointment. Blood and urine cultures were taken and she was admitted to the hospital with a serum creatinine of 3.1 mg/dl. Her clearance was 21.4 L/h. How would you adjust S.K. s cyclosporine dose in order to increase the cyclosporine concentration to approximately 250 µg/l? (6 pts.) A. 500 mg q12h B. 190 mg q12h C. 115 mg q12h D. 115 mg q8h E. 380 mg q12h Key: E or B Vd 4.5L / kg weight 4.5L / kg 54kg 243L CL 21.4L / h 1 k e 0.088h Vd 243L ke τ Cp Vd e µg L L e Dose ss,min / ke τ F S e e ( ) ( ) 39609µg µg mg mg q12h E Dose Cpss, ave CL τ F S 250µg / L 21.4L / h 12h µg µg 214mg 190mg q12h B Final

20 18. K.E., a 42-year-old, 62 kg female with a serum creatinine of 1.2 mg/dl, is to receive 12 gm IV methotrexate infused over four hours. Calculate the methotrexate concentration 12 hours after the end of the infusion. (8 pts.) A µm B µm C µm D µm E µm Key: C ( 140 age) weight ( ) 62 CL Cr 59.6mL / min 3.6L / h 85 SeCr CL 1.6 CLCr L / h 5.76L / h Dose Cp(12h) CL T k 12000mg e T ke t ( 1 e ) e ( 1 e ) e 520.8mg / L L / h 4h 19.7mg / L Cp( mg / L) 19.7mg / L Cp( 12h) µm 43. 4µM Final