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 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

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)

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

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

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

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

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

EEG Response as a fraction of IC 50 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: , 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 l 95 Subjects, ages 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.

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

Three Compartment Model

Remifentanil vs. other opioids Minto et al, Anesthesiology, in press Minutes since bolus injection Percent of peak plasma opioid concentration fentanyl sufentanil alfentanil remifentanil

Three Compartment Model plus an “Effect Site”

Remifentanil vs. other opioids Minto et al, Anesthesiology, in press Minutes since bolus injection Percent of peak effect site opioid concentration fentanyl sufentanil alfentanil remifentanil

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 Minutes required for a given percent decrease in effect site concentration Minutes since beginning of infusion % decrease 50% decrease 80% decrease fentanyl alfentanil sufentanil remifentanil Shafer SL, ASA Refresher Course, Chapter 19, 1996

20% effect site decrement curves Minutes required Minutes since beginning of infusion fentanyl alfentanil sufentanil remifentanil Shafer SL, ASA Refresher Course, Chapter 19, 1996

20% effect site decrement curves Minutes required Minutes since beginning of infusion fentanyl alfentanil sufentanil remifentanil 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

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

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

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

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

Age Related Changes In Bolus Dose Parameters Age (years) Parameter V 1 (liters) t 1/2 k e0 (min) t peak (min) Vd pe (liters) EC 50 (ng ml ) Bolus to peak at EC 50 (  g) Minto et al, Anesthesiology, in press

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 Bolus dose (  g) Age (years) LBM 75kg 35kg Minto et al, Anesthesiology, in press

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

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 Infusion rate (  g/min) Age (years) LBM 75kg 35kg Minto et al, Anesthesiology, in press

Age does not affect average time to emergence Minto et al, Anesthesiology, in press 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%

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 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 Propofol Concentration (  g/ml) Alfentanil Concentration (ng/ml) Intubation Maintenance Emergence

“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

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

Propofol/Opioid Time to Awakening 600 Time (Minutes) Time (Minutes) Alfentanil Technique Remifentanil Technique Shafer SL, ASA Refresher Course, Chapter 19, 1996

Propofol/Opioid Infusion rates 600 Time (Minutes) Propofol (  g/kg/min) Remifentanil (ng/kg/min) Time (Minutes) Propofol (  g/kg/min) Alfentanil (ng/kg/min) Shafer SL, ASA Refresher Course, Chapter 19, 1996 Alfentanil Technique Remifentanil Technique

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

Propofol/Opioid Percent Decrease on Emergence 600 Time (Minutes) Time (Minutes) Propofol Remifentanil Propofol Alfentanil Shafer SL, ASA Refresher Course, Chapter 19, 1996 Alfentanil Technique Remifentanil Technique

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

ULTIVA Dosing Guide