Early Clinical DevelopmentEarly 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 GoalsLecture 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

AcknowledgementsAcknowledgements

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 Alfentanil Clinical Concentration vs ResponseConcentration vs Response

Ausems ME, Hug CC, Stanski DR, Burm AGL: Anesthesiology 65:362-373, 1986

Alfentanil Concentration-Alfentanil Concentration-Response RelationshipsResponse Relationships

ALFENTANIL (ng•ml

-1

)

0 100 200 300 400 500 600 700 800

PR

OB

AB

ILIT

Y o

f RE

SP

ON

SE

(%

)

0

25

50

75

100

Tra

chea

l Int

ubat

ion

*

*With 66% N2O

EEG

Ven

tilat

ion

Ski

n In

cisi

on

*

Ski

n C

losu

re

*

Abd

omin

al S

urge

ry

*Ausems et al

Egan et al

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

Opioid Therapeutic RangesOpioid Therapeutic Ranges

Adequate ventilationon emergence:

N2O Only:N2O/Potent vapor:

Maintenance:

O2/N2O Only:with Thiopental:

Intubation:AlfentanilSufentanil

0.1 1 10 100 1000

Fentanyl

Effect Site Opioid Concentration (ng/ml)

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

Time (sec)0 1 2 3 4 5

-60

-40

-20

0

20

40

60

EE

G (V

)

Awake EEGAwake EEG

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

Profound Opioid EEG Effect

Time (sec)

0 1 2 3 4 5

-60-40-20

0204060

EE

G (V

)

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

EEG Time Course with FentanylEEG Time Course with Fentanyl

Scott J, Ponganis KV, Stanski DR. Anesthesiology 62:234-241, 1985

EEG Time Course with AlfentanilEEG Time Course with Alfentanil

Scott J, Ponganis KV, Stanski DR. Anesthesiology 62:234-241, 1985

Fentanyl, Alfentanil, Sufentanil EEGFentanyl, Alfentanil, Sufentanil EEG

0.1 1 10 100 1000

0.00

0.25

0.50

0.75

1.00

Effect Site Opioid Concentration (ng/ml)

Fra

ctio

nal R

espo

nse

Suf

enta

nil

Alf

enta

nil

Fen

tany

l

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

EEG Response as a fraction of ICEEG Response as a fraction of IC5050

Effect Site Opioid Concentration

Fra

ctio

nal R

espo

nse

Sufentanil Alfentanil

0.0 0.5 1.0 1.5 2.0

0.00

0.25

0.50

0.75

1.00

As a Fraction of IC50

Fentanyl

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

EEG vs Therapeutic RangesEEG vs Therapeutic Ranges

EE

G R

espo

nse

Adequate ventilationon emergence:

N2O Only:N2O/Potent vapor:

Maintenance:

O2/N2O Only:with Thiopental:

Intubation:AlfentanilSufentanil

0.1 1 10 100 10000.00

0.25

0.50

0.75

1.00

Fentanyl

Effect Site Opioid Concentration (ng/ml)Billard V, Shafer SL. Control and Automation in Anesthesia. 1995, Springer

EEG vs Opioid Therapeutic RangesEEG vs Opioid Therapeutic Ranges

0.1 1 10

0.00

0.25

0.50

0.75

1.00

as a Fraction of the IC50

Effect Site Opioid Concentration

EE

G R

espo

nse

Adequate ventilationon emergence:

N2O Only:N2O/Potent vapor:

Maintenance:

O2/N2O Only:with Thiopental:

Intubation:

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

EEG Time Course with RemifentanilEEG Time Course with Remifentanil

Egan, et al. Anesthesiology 84:881-833, 1996

Fentanyl Congener EEG Pharmacodynamic

ParametersDrug E0 Emax

EC50 T1/2ke0

(Hz) (Hz) (ngml-1) (min)

FentanylScott et al 19.21.6 14.11.8 4.91.0 6.91.5 6.41.3Scott et al 25.03.0 16.83.5 6.21.8 8.12.2 6.61.3Scott & Stanski 18.92.1 13.02.7 4.31.3 7.82.6 4.71.5Lemmens et al 19.04.0 12.03.0 4.03.0 9.88.3 5.42.1

AlfentanilScott et al 20.13.4 14.73.1 4.81.5 520163 1.10.3Scott & Stanski 19.23.4 13.54.1 4.82.4 479271 0.90.3Egan et al 18.04.2 13.03.3 8.37.5 376159 1.00.8Lemmens et al 21.02.0 15.02.0 6.02.0 577273 0.60.4

SufentanilScott et al 24.32.7 16.52.5 3.10.9 0.680.31 6.22.8

RemifentanilEgan et al 19.02.9 13.83.8 4.32.0 19.95.2 0.80.4

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

Remifentanil Therapeutic RangesRemifentanil Therapeutic Ranges

EE

G R

espo

nse

0.1 1 10 100 10000.00

0.25

0.50

0.75

1.00

Effect Site Opioid Concentration (ng/ml)

AFS

Adequate ventilationon emergence:

N2O Only:N2O/Potent vapor:

Maintenance:

O2/N2O Only:with Thiopental:

Intubation:

Remifentanil DosingRemifentanil DosingBased on Phase I PK/PDBased on Phase I PK/PD

Remifentanil Dosing: Induction of AnesthesiaTechnique Dose

(g) With Thiopental 150-225 With Nitrous Oxide Only 300-450

Remifentanil Dosing: Anesthesia MaintenanceTechnique Rate (g/min)

5-15 min Beyond 15 min With Isoforane/Nitrous Oxide 12-30 10-25 With Nitrous Oxide Only 12-70 10-60 With Oxygen Only 100-450 90-400

Remifentanil Time CourseRemifentanil Time Course

TIME (min)

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150

RE

MIF

EN

TA

NIL

(ng

•ml-1

)

0

2

4

6

8

10

12

14

16

181.7 g•kg

-1 0.8-1.0 g•kg

-1•min

-1

0.1 - 0.2 g•kg-1

•min-1

0.3 g•kg-1

0.3 g•kg-1

•min-1

0.3 g•kg-1

0.4 - 0.5 g•kg-1

•min-1

0.1 - 0.2 g•kg-1

•min-1

Prep

Incision

Intra-abdominal

Intubation

Closure

PACU Analgesia

0.025 - 0.1 g•kg-1

•min-1

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

Relative Therapeutic WindowsRelative Therapeutic Windows

CONCENTRATION (ng•ml-1

)

0.01 0.1 1 10 100 1000

ANALGESIA50% MAC REDUCTIONPROPOFOL (high)

PROPOFOL (low)

VENTILATION

PERIPHERAL SUGERY*CAVITY SURGERY*

SKIN CLOSURE*SKIN INCISION*

TRACHEAL INTUBATION*

ALFENTANIL

SUFENTANIL

FENTANYL

EEG EC50

*With 66% N2O

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

Opioid Fingerprint, 1997Opioid Fingerprint, 1997

PROPORTION OF EEG EC 50 (%)

0 10 20 30 40 50 60 70 80 90 100 110

ANALGESIA

50% MAC REDUCTIONPROPOFOL (high)

PROPOFOL (low)

VENTILATION

PERIPHERAL SUGERY*CAVITY SURGERY*

SKIN CLOSURE*

SKIN INCISION*

TRACHEAL INTUBATION*

*With 66% N2O

EEG EC50

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

Remifentanil FingerprintRemifentanil Fingerprint

CONCENTRATION (ng•ml-1

)

0 2 4 6 8 10 12 14 16 18 20 22

ANALGESIA50% MAC REDUCTIONPROPOFOL (high)PROPOFOL (low)

VENTILATIONPERIPHERAL SUGERY*CAVITY SURGERY*

SKIN CLOSURE*SKIN INCISION*TRACHEAL INTUBATION*

REMIFENTANIL (predicted)

REMIFENTANIL (measured)

*With 66% N2O

EEG EC50

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