Pharmacy 732

1. Pharmacy 732 Winter 2003

2. Instructors • William Hayton Pharmaceutics • James Coyle PPAD • Cari Brackett PPAD • Kristin Lugo PPAD • Juhyun Kim Pharmaceutics

3. Contact Information

4. Exams • 3 Exams, 100 points each • Exam 1: Tues. Jan. 28, • Exam 2: Tues. Feb. 18, • Exam 3: Tue. March 18, 9:30 – 11:18 • Quizzes, – seven total, 15 points each, drop the lowest score - 90 points • Workshop participation - 10 points • Total:---------------------------------- 400 points

5. Grading Total Points  4

6. Remediation and Make-Up • Exams 1 & 2 will be offered again during the 10th week class. • Remediation • Open to all students; manditory for students scoring <67. • Scoring: 0.2 x first score + 0.8 x second score • (0.2)(65) + (0.8)(85) = 81 • Make-Up • If exam was missed for a qualified reason, full score will count; if not, remediation scoring will be used with the first score being zero.

7. Post-Course Remediation • Course average between 60.0 and 66.9 • Eligible to take a comprehensive exam over Pharmacy 732 during workshop of the first week of Pharmacy 733. • 67.0: C- for the course • <67.0: E for the course • Course average <60 • No post-course remediation allowed and E grade stands.

8. Workshops • Monday Afternoon, 1:30 – 3:18 • Rm. 550 • Rm. 257 • Wednesday Afternoon 1:30 – 3:18 • Rm. 550 Parks Hall • Rm. 257 Parks Hall

9. Course Materials • Clinical Pharmacokinetics, Rowland and Tozer, third edition • Calculator • Semilog graph paper • Course Pack

10. Classroom Conduct • Quiet is appreciated • Cell phones turned off • Pagers in quiet mode • Refrain from exiting and re-entering

11. Academic Misconduct: Exams • No caps • No use of memory in calculators • No PDAs, laptops, etc. • No exchanging information with others • No cell phones or pagers in “on” mode • No crib notes, cheat sheets, etc.

13. WebCT • Course Materials • Slides from class • Narrated slides from class • Reference materials; e.g., PK parameters • Exam Keys old and current • Quiz Keys old and current • Bulletin board • Email • Quiz and exam scores; i.e., grade book • Self tests • Student home page - optional

14. WebCT Logon • (1) Open a web browser and go to: http://class.osu.edu • (2) Log on: • Enter your “username” and “password.” •   Username = lastname.123  (all lowercase, No CAPITAL LETTERS!) • Example: If your E-mail address is smith.303@osu.edu = Username is “smith.303” •  Password = same one you use to check your OSU e-mail, to register online for classes, and to enable Internet access in OIT student computer labs.

15. Dosing Regimen Design Infusion regimen

16. Why is a dosing regimen necessary? • To replace the drug that the body eliminates. How can drug be replaced? • Continuously or intermittently.

17. Continuous Input • Learning Objectives • input rate to achieve a desired plasma concentration. • kinetics of accumulation; i.e., how long to steady state. • loading dose. • determination of CL, V, KE and t1/2.

18. Examples of continuous input • i.v. drip • i.v. infusion • transdermal patch • sustained release oral dosage forms • Ocusert • Norplant

19. Ko v CL Kinetics of continuous input A = amount of drug in body Cp = plasma concentration Ko = input rate (amt/time) KE = elimination rate constant, (CL/V) dA/dt = rate in - rate out dA/dt = Ko - KEA A = V x Cp and KEV = CL dA/dt = Ko - CL•Cp dA/dt = 0 at a plateau Cp Rate In = Rate Out Ko = CL •Cp,ss Cp,ss = Ko/CL

20. young Ln Cp old Time Example: Diazepam Cp,t profile in young and old: DR adjustment? What’s different? Herman and Wilkinson. Br. J. Clin. Pharmacol. 42:147,1996. #2919

21. Principles • When infused at the same rate (one compartment model assumed): • all drugs with the same half life will have the same steady-state amount of drug in the body. • all drugs with the same clearance will have the same steady-state plasma concentration.

22. Accumulation Kinetics

23. Time to steady state 3.3 t1/2 is time to 90% of Cp,ss t = nt1/2 where n = no. of half lives that have passed

24. Example This drug has a V = 45 L and a CL = 12 L/h. What infusion rate is needed to achieve a Cp,ss of 25 mg/L? Ko = CL x Cp,ss = 12 L/h x 25 mg/L = 300 mg/h How long will it take to get to 90% of steady state? t1/2 = ln 2 V/CL = (0.693)(45)/(12) = 2.6 h t90% = 3.3 t1/2 = (3.3)(2.6) = 8.6 h How much drug is in the body at steady state? Ass = Cp,ssV = 45 L x 25 mg/L = 1,125 mg

25. Summary

26. V Ass t90% Ko CL Css Diagram VP, VE, VR RE/I, fur, fup QH, fup, CLint,u GFR, etc.

27. Review With a constant rate of input, Ko Rate Out Rate In = _______ CL Rate In = Css x ___ KE Rate In = Ass x ___ All drugs with same CL will have same ____ Css Ass All drugs with same t1/2 will have same ____

28. Post-Infusion Cp Profile

29. Post-Infusion Cp Profile

30. CL by 25% Cp V by 25% Ko by 25% Time Changing to a new Cp,ss

31. Bolus and Infusion A “loading dose” may be used to start at steady state immediately. Loading Dose = Ass = Ko/KE = CssV

32. Rowland and Tozer, Figure 6-5. p. 74

33. Time to Steady State 3.3 t1/2 is time to 90% of Cp,ss. When Cp,0 is 0, this is within ±10% of Cp,ss. When Cp,0 is  0, the time to ±10% of Cp,ss differs from the t90%. What is the appropriate endpoint for calculation of the time to steady state?

34. Calculation of time to ±10% Cp,ss Plasma concentration at any time after bolus + infusion: Given Cp,0 and Css, the time to reach any Cp can be calculated from:

35. Example Cp,0 = 500 mg/L and Css = 100 mg/L, how long does it take to reach 110 mg/L? (i.e., 110% of Css) (1/2)n = (100 – 110)/(100 – 500) = -10/-400 = 0.025 (n)[ln (0.5)] = ln (0.025) n = ln (0.025) / ln (0.5) = 5.32 half lives 140 mg/L What would be the Cp after 3.3 half lives?

36. -2.3 slope = KE Log (Cp,ss - Cp) Time Assessment of PK parameters 1. CL = Ko / Cp,ss 2. Get KE from the slope of a semilog plot of (Cp,ss – Cp) vs. t. 3. V = CL / KE