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

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

4. Alfentanil Clinical Concentration vs Response
Ausems ME, Hug CC, Stanski DR, Burm AGL:
Anesthesiology 65: , 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, , 1992

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

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

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

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

12. EEG Response as a fraction of IC50
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: , 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
95 Subjects, ages 20-85
Study performed by
Talmage Egan, M.D.
Harry Lemmens, M.D.
Charles Minto, M.D.
Thomas Schnider, M.D.
Elizabeth Youngs, M.D.
Analysis by Charles Minto, M.D.

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

25. Three Compartment Model

26. Remifentanil vs. other opioids
100 10
Percent of peak plasma opioid concentration
fentanyl 1
sufentanil
alfentanil
remifentanil
0.1
120
240
360
480
600
Minutes since bolus injection
Minto et al, Anesthesiology, in press

27. Three Compartment Model plus an “Effect Site”

28. Remifentanil vs. other opioids
100
sufentanil 80
fentanyl 60
Percent of peak effect site opioid concentration 40
alfentanil 20
remifentanil 2 4 6 8 10
Minutes since bolus injection
Minto et al, Anesthesiology, in press

29. Remifentanil vs. other opioids
Recovery from remifentanil is unlike that seen with any other opioid
The time to a given decrease in effect site concentration is constant over time
no accumulation 60
fentanyl 40
20% decrease 20
alfentanil
sufentanil
remifentanil
120
fentanyl 90
alfentanil
Minutes required for a given percent
decrease in effect site concentration 60
50% decrease 30
sufentanil
remifentanil
300
fentanyl
240
alfentanil
180
120
80% decrease
sufentanil 60
remifentanil
120
240
360
480
600
Minutes since beginning of infusion
Shafer SL, ASA Refresher Course, Chapter 19, 1996

30. 20% effect site decrement curves60
fentanyl 40
Minutes required
alfentanil 20
sufentanil
remifentanil
120
240
360
480
600
Minutes since beginning of infusion
Shafer SL, ASA Refresher Course, Chapter 19, 1996

31. 20% effect site decrement curves60
fentanyl 40
Minutes required
alfentanil 20
sufentanil
remifentanil
120
240
360
480
600
Minutes since beginning of infusion
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. V1 and Clearance decrease with age
V1 decreases about 20% from age 20 to 80
Common finding for anesthetic drugs
Clearance decreases about 30% from age 20 to 80
Mechanism unknown
Minto et al, Anesthesiology, in press

35. EC50 decreases with age EC50 is a measure of brain sensitivity
Decreased EC50 means increased sensitivity
Decreased EC50 with age also reported for:
fentanyl
alfentanil
sufentanil

36. t 1/2 ke0 increases with age
t 1/2 ke0 is the time required for the brain to equilibrate with the plasma
an increase in t 1/2 ke0 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. Bolus doses should be reduced by 50% in the elderly
The reduction in bolus dose is because of the 50% increase in sensitivity in the elderly
Adjusting the bolus for age is at least as important as adjusting it for body weight
400 g) m
300
LBM
200
75kg
Bolus dose (
100
35kg 20 40 60 80
Age (years)
Minto et al, Anesthesiology, in press

39. Infusion rates should be reduced by 2/3’s in the elderly
The infusion rate is decreased because of increased sensitivity and decreased clearance
Adjusting the infusion rate for age is more important than adjusting it for weight 60 50
g/min) m 40
LBM 30 20
75kg
Infusion rate ( 10
35kg 20 40 60 80
Age (years)
Minto et al, Anesthesiology, in press

40. Age does not affect average time to emergence15
80 yrs
80%
20 yrs 10
Minutes required for a given
decrease in effect site concentration
80 yrs 5
50%
20 yrs
80 yrs
20%
20 yrs
300
600
Infusion duration (minutes)
Minto et al, Anesthesiology, in press

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

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

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

44. Propofol/Alfentanil Interaction
Adapted from Vuyk et al, Anesthesiology 83:8-22, 1995
Characterizes the concentrations for
intubation
maintenance
on emergence
Concentrations are 50% response level
400
Intubation
300
Maintenance
Alfentanil Concentration (ng/ml)
200
Emergence
100 2 4 6 8 10
Propofol Concentration (mg/ml)

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

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

47. Propofol/Opioid Time to Awakening
Alfentanil Technique
Remifentanil Technique 20 15 10 5
120
240
360
480
600
120
240
360
480
600
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996

48. Propofol/Opioid Infusion rates
Alfentanil Technique
Remifentanil Technique
400
300
Remifentanil (ng/kg/min)
Alfentanil (ng/kg/min)
200
Propofol (mg/kg/min)
100
Propofol (mg/kg/min)
120
240
360
480
600
120
240
360
480
600
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996

49. Propofol/Opioid Propofol Levels (mg/ml)
Alfentanil Technique
Remifentanil Technique 6 4
Maintenance
Maintenance 2
Emergence
Emergence
120
240
360
480
600
120
240
360
480
600
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996

50. Propofol/Opioid Percent Decrease on Emergence
Alfentanil Technique
Remifentanil Technique
100 75
Remifentanil
Propofol 50
Propofol 25
Alfentanil
120
240
360
480
600
120
240
360
480
600
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996

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

52. ULTIVA Dosing Guide