1. Early Clinical Development High Resolution PK/PD in Phase I to Guide Subsequent Development: Experience with Remifentanil Steven L. Shafer, M.D. Palo Alto VA Health Care System Stanford University School of Medicine

2. Lecture Goals l Explain opioid concentration/effect relationships l Explain EEG measures of opioid drug effect l Introduce opioid “fingerprint” using EEG as a surrogate measure of drug effect l Explain how the EEG established remifentanil therapeutic windows in Phase I l Demonstrate how Phase I PK/PD affected Phase II and III study design and drug labeling

3. Acknowledgements l Donald Stanski, M.D. (Stanford) l Keith Muir, Ph.D. (Glaxo) l Robert Powell, M.D. (Glaxo) l Talmage Egan, M.D. (Stanford) l Charles Minto, M.D. (Stanford) l Thomas Schinder, M.D. (Stanford) l Dan Spyker, M.D. (FDA)

4. Alfentanil Clinical Concentration vs Response Ausems ME, Hug CC, Stanski DR, Burm AGL: Anesthesiology 65:362-373, 1986

5. Alfentanil Concentration- Response Relationships Egan, et al. The role of the EEG in Remifentanil Development.

6. Opioid Therapeutic Ranges Billard V, Shafer SL. Control and Automation in Anesthesia. 1995, Springer

7. Awake EEG Gregg K, Varvel JR, Shafer SL. J Pharmacokinet Biopharm 20, 611-635, 1992

8. Profound Opioid EEG Effect Gregg K, Varvel JR, Shafer SL. J Pharmacokinet Biopharm 20, 611-635, 1992

9. EEG Time Course with Fentanyl Scott J, Ponganis KV, Stanski DR. Anesthesiology 62:234-241, 1985

10. EEG Time Course with Alfentanil Scott J, Ponganis KV, Stanski DR. Anesthesiology 62:234-241, 1985

11. Fentanyl, Alfentanil, Sufentanil EEG Billard V, Shafer SL. Control and Automation in Anesthesia. 1995, Springer

12. EEG Response as a fraction of IC 50 Billard V, Shafer SL. Control and Automation in Anesthesia. 1995, Springer

13. EEG vs Therapeutic Ranges Billard V, Shafer SL. Control and Automation in Anesthesia. 1995, Springer

14. EEG vs Opioid Therapeutic Ranges Billard V, Shafer SL. Control and Automation in Anesthesia. 1995, Springer

15. EEG Time Course with Remifentanil Egan, et al. Anesthesiology 84:881-833, 1996

16. Fentanyl Congener EEG Pharmacodynamic Parameters Egan, et al. The role of the EEG in Remifentanil Development.

17. Remifentanil Therapeutic Ranges

18. Remifentanil Dosing Based on Phase I PK/PD

19. Remifentanil Time Course Egan, et al. The role of the EEG in Remifentanil Development.

20. Relative Therapeutic Windows Egan, et al. The role of the EEG in Remifentanil Development.

21. Opioid Fingerprint, 1997 Egan, et al. The role of the EEG in Remifentanil Development.

22. Remifentanil Fingerprint Egan, et al. The role of the EEG in Remifentanil Development.

23. Remifentanil in the Elderly l 95 Subjects, ages 20-85 l Study performed by l Talmage Egan, M.D. l Harry Lemmens, M.D. l Charles Minto, M.D. l Thomas Schnider, M.D. l Elizabeth Youngs, M.D. l Analysis by Charles Minto, M.D.

24. The remifentanil “Unit Disposition Function” l Expected plasma concentration –following bolus of 1 unit l Data from 65 adults –Age range: 20-85 yrs l Note very rapid decrease l Less variability than with other anesthetic drugs Minto et al, Anesthesiology, in press

25. Three Compartment Model

26. Remifentanil vs. other opioids Minto et al, Anesthesiology, in press Minutes since bolus injection 0120 240 360480600 Percent of peak plasma opioid concentration 0.1 1 10 100 fentanyl sufentanil alfentanil remifentanil

27. Three Compartment Model plus an “Effect Site”

28. Remifentanil vs. other opioids Minto et al, Anesthesiology, in press Minutes since bolus injection 02 46810 Percent of peak effect site opioid concentration 0 20 40 60 80 100 fentanyl sufentanil alfentanil remifentanil

29. Remifentanil vs. other opioids l Recovery from remifentanil is unlike that seen with any other opioid l The time to a given decrease in effect site concentration is constant over time l no accumulation 0 20 40 60 Minutes required for a given percent decrease in effect site concentration 0 30 60 90 120 Minutes since beginning of infusion 0120240360480600 0 60 120 180 240 300 20% decrease 50% decrease 80% decrease fentanyl alfentanil sufentanil remifentanil Shafer SL, ASA Refresher Course, Chapter 19, 1996

30. 20% effect site decrement curves 0 20 40 60 Minutes required Minutes since beginning of infusion 0120 240360480600 fentanyl alfentanil sufentanil remifentanil Shafer SL, ASA Refresher Course, Chapter 19, 1996

31. 20% effect site decrement curves 0 20 40 60 Minutes required Minutes since beginning of infusion 0120 240360480600 fentanyl alfentanil sufentanil remifentanil Shafer SL, ASA Refresher Course, Chapter 19, 1996

32. 50% effect site decrement curves Minutes required Minutes since beginning of infusion Shafer SL, ASA Refresher Course, Chapter 19, 1996

33. 80% effect site decrement curves Minutes required Minutes since beginning of infusion Shafer SL, ASA Refresher Course, Chapter 19, 1996

34. V 1 and Clearance decrease with age l V 1 decreases about 20% from age 20 to 80 –Common finding for anesthetic drugs l Clearance decreases about 30% from age 20 to 80 –Mechanism unknown Minto et al, Anesthesiology, in press

35. EC 50 decreases with age l EC 50 is a measure of brain sensitivity l Decreased EC 50 means increased sensitivity l Decreased EC 50 with age also reported for: l fentanyl l alfentanil l sufentanil

36. t 1/2 k e0 increases with age l t 1/2 k e0 is the time required for the brain to equilibrate with the plasma l an increase in t 1/2 k e0 would be expected to result in a slower onset of drug effect

37. Age delays onset but does not affect peak concentration Minto et al, Anesthesiology, in press

38. Age Related Changes In Bolus Dose Parameters Age (years) 20 5080 Parameter V 1 (liters) 5.5 5.14.3 t 1/2 k e0 (min) 0.94 1.322.20 t peak (min) 1.22 1.572.26 Vd pe (liters) 17.35 16.9717.30 EC 50 (ng ml ) 16.1 11.67.2 Bolus to peak at EC 50 (  g) 279 197124 Minto et al, Anesthesiology, in press

39. Bolus doses should be reduced by 50% in the elderly l The reduction in bolus dose is because of the 50% increase in sensitivity in the elderly l Adjusting the bolus for age is at least as important as adjusting it for body weight 0 100 200 300 400 2040 6080 Bolus dose (  g) Age (years) LBM 75kg 35kg Minto et al, Anesthesiology, in press

40. Age Related Changes In Infusion Rate Parameters Minto et al, Anesthesiology, in press

41. Infusion rates should be reduced by 2/3’s in the elderly l The infusion rate is decreased because of increased sensitivity and decreased clearance l Adjusting the infusion rate for age is more important than adjusting it for weight 20406080 0 10 20 30 40 50 60 Infusion rate (  g/min) Age (years) LBM 75kg 35kg Minto et al, Anesthesiology, in press

42. Age does not affect average time to emergence Minto et al, Anesthesiology, in press 0 300600 0 5 10 15 20 yrs 80 yrs 20 yrs 80 yrs 20 yrs 80 yrs Infusion duration (minutes) Minutes required for a given decrease in effect site concentration 80% 50% 20%

43. Age effects on bolus dose Minto et al, Anesthesiology, in press

44. Age effects on infusion rate Minto et al, Anesthesiology, in press

45. Age affects variability in time to emergence Minto et al, Anesthesiology, in press

46. Propofol/Alfentanil Interaction l Adapted from Vuyk et al, Anesthesiology 83:8- 22, 1995 l Characterizes the concentrations for l intubation l maintenance l on emergence l Concentrations are 50% response level 0 100 200 300 400 0246810 Propofol Concentration (  g/ml) Alfentanil Concentration (ng/ml) Intubation Maintenance Emergence

47. “Optimal” Propofol/Alfentanil l Infusion rates for propofol and alfentanil l Propofol levels during maintenance and at emergence from anesthesia l Alfentanil concentrations during maintenance and at emergence l Time from ending the infusion to awakening from anesthesia l The percent decrease in concentration required for emergence from anesthesia Stanski and Shafer: Anesthesiology 83:1-5, 1995

48. Propofol/Opioid Technique Stanski and Shafer: Anesthesiology 83:1-5, 1995 Shafer SL, ASA Refresher Course, Chapter 19, 1996

49. Propofol/Opioid Time to Awakening 600 Time (Minutes) 120240360480600 Time (Minutes) 0120240360480 0 5 10 15 20 Alfentanil Technique Remifentanil Technique Shafer SL, ASA Refresher Course, Chapter 19, 1996

50. Propofol/Opioid Infusion rates 600 Time (Minutes) 120240360480600 Propofol (  g/kg/min) Remifentanil (ng/kg/min) Time (Minutes) 0120240360480 0 100 200 300 400 Propofol (  g/kg/min) Alfentanil (ng/kg/min) Shafer SL, ASA Refresher Course, Chapter 19, 1996 Alfentanil Technique Remifentanil Technique

51. Propofol/Opioid Propofol Levels (  g/ml) 600 Time (Minutes) 120240360480600 Time (Minutes) 0120240360480 Maintenance Emergence 2 4 Maintenance Emergence 6 0 Shafer SL, ASA Refresher Course, Chapter 19, 1996 Alfentanil Technique Remifentanil Technique

52. Propofol/Opioid Percent Decrease on Emergence 600 Time (Minutes) 120240360480600 Time (Minutes) 0120240360480 Propofol Remifentanil 0 25 50 75 100 Propofol Alfentanil Shafer SL, ASA Refresher Course, Chapter 19, 1996 Alfentanil Technique Remifentanil Technique

53. Propofol/Remifentanil TIVA Shafer SL, ASA Refresher Course, Chapter 19, 1996 l Remifentanil: 0.25  g/kg/min l Propofol: 80  g/kg/min l Requires controlled ventilation l Little tolerance for interruption of remifentanil or propofol infusion

54. ULTIVA Dosing Guide