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Early Clinical Development

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. Lecture Goals. Explain opioid concentration/effect relationships

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Early Clinical Development

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  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 65:362-373, 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 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 84:881-833, 1996

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

  17. Remifentanil Therapeutic Ranges

  18. Remifentanil DosingBased 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: 20-85 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 0.1 360 480 600 240 0 120 Minutes since bolus injection Minto et al, Anesthesiology, in press

  27. Three Compartment Modelplus an “Effect Site”

  28. Remifentanil vs. other opioids 100 sufentanil 80 fentanyl 60 Percent of peak effect site opioid concentration 40 alfentanil 20 remifentanil 0 4 6 8 10 0 2 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 alfentanil 20 sufentanil 0 remifentanil 120 fentanyl 90 alfentanil Minutes required for a given percent decrease in effect site concentration 60 50% decrease sufentanil 30 remifentanil 0 300 fentanyl 240 alfentanil 180 80% decrease 120 sufentanil 60 remifentanil 0 0 120 240 360 480 600 Minutes since beginning of infusion Shafer SL, ASA Refresher Course, Chapter 19, 1996

  30. 20% effect sitedecrement curves 60 fentanyl 40 Minutes required alfentanil 20 sufentanil remifentanil 0 240 360 480 600 0 120 Minutes since beginning of infusion Shafer SL, ASA Refresher Course, Chapter 19, 1996

  31. 20% effect sitedecrement curves 60 fentanyl 40 Minutes required alfentanil 20 sufentanil remifentanil 0 240 360 480 600 0 120 Minutes since beginning of infusion Shafer SL, ASA Refresher Course, Chapter 19, 1996

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

  33. 80% effect sitedecrement 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 ofbrain 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 brainto equilibrate withthe plasma • an increase in t 1/2 ke0would be expected toresult in a slower onsetof 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) 300 m LBM 200 75kg Bolus dose ( 100 35kg 0 60 80 20 40 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) 40 m LBM 30 75kg 20 Infusion rate ( 10 35kg 0 20 40 60 80 Age (years) Minto et al, Anesthesiology, in press

  40. Age does not affect average time to emergence 15 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 0 300 600 0 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 400 • Adapted from Vuyk et al, Anesthesiology 83:8-22, 1995 • Characterizes the concentrations for • intubation • maintenance • on emergence • Concentrations are 50% response level Intubation 300 Maintenance 200 Alfentanil Concentration (ng/ml) Emergence 100 0 0 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/OpioidTime to Awakening Alfentanil Technique Remifentanil Technique 20 15 10 5 0 0 120 240 360 480 600 120 240 360 480 600 Time (Minutes) Time (Minutes) Shafer SL, ASA Refresher Course, Chapter 19, 1996

  48. Propofol/OpioidInfusion 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) 0 0 120 240 360 480 600 120 240 360 480 600 Time (Minutes) Time (Minutes) Shafer SL, ASA Refresher Course, Chapter 19, 1996

  49. Propofol/OpioidPropofol Levels (mg/ml) Alfentanil Technique Remifentanil Technique 6 4 Maintenance Maintenance 2 Emergence Emergence 0 0 120 240 360 480 600 120 240 360 480 600 Time (Minutes) Time (Minutes) Shafer SL, ASA Refresher Course, Chapter 19, 1996

  50. Propofol/OpioidPercent Decrease on Emergence Alfentanil Technique Remifentanil Technique 100 75 Remifentanil Propofol 50 Propofol 25 Alfentanil 0 0 120 240 360 480 600 120 240 360 480 600 Time (Minutes) Time (Minutes) Shafer SL, ASA Refresher Course, Chapter 19, 1996

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