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 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

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)

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

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

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

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

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

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

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

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

EEG Response as a fraction of IC50 Billard V, Shafer SL. Control and Automation in Anesthesia. 1995, Springer

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

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

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

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

Remifentanil Therapeutic Ranges

Remifentanil Dosing Based on Phase I PK/PD

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

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

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

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

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.

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

Three Compartment Model

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

Three Compartment Model plus an “Effect Site”

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

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

20% effect site decrement curves 60 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

20% effect site decrement curves 60 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

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

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

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

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

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

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

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

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

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 300 600 Infusion duration (minutes) Minto et al, Anesthesiology, in press

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

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

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

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)

“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

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

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

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

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

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

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

ULTIVA Dosing Guide