Early Clinical Development High Resolution PK/PD in Phase I to Guide Subsequent Development: Experience with Remifentanil Steven L. Shafer, M.D. Palo Alto.

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Presentation transcript:

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.