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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.