Early Clinical Development

1
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
2
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

3
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)

4
Alfentanil Clinical Concentration vs Response
Ausems ME, Hug CC, Stanski DR, Burm AGL
Anesthesiology 65362-373, 1986
5
Alfentanil Concentration-Response Relationships
Egan, et al. The role of the EEG in Remifentanil
Development.
6
Opioid Therapeutic Ranges
Billard V, Shafer SL. Control and Automation in
Anesthesia. 1995, Springer
7
Awake EEG
Gregg K, Varvel JR, Shafer SL. J Pharmacokinet
Biopharm 20, 611-635, 1992
8
Profound Opioid EEG Effect
Gregg K, Varvel JR, Shafer SL. J Pharmacokinet
Biopharm 20, 611-635, 1992
9
EEG Time Course with Fentanyl
Scott J, Ponganis KV, Stanski DR. Anesthesiology
62234-241, 1985
10
EEG Time Course with Alfentanil
Scott J, Ponganis KV, Stanski DR. Anesthesiology
62234-241, 1985
11
Fentanyl, Alfentanil, Sufentanil EEG
Billard V, Shafer SL. Control and Automation in
Anesthesia. 1995, Springer
12
EEG Response as a fraction of IC50
Billard V, Shafer SL. Control and Automation in
Anesthesia. 1995, Springer
13
EEG vs Therapeutic Ranges
Billard V, Shafer SL. Control and Automation in
Anesthesia. 1995, Springer
14
EEG vs Opioid Therapeutic Ranges
Billard V, Shafer SL. Control and Automation in
Anesthesia. 1995, Springer
15
EEG Time Course with Remifentanil
Egan, et al. Anesthesiology 84881-833, 1996
16
Fentanyl Congener EEG Pharmacodynamic Parameters
Egan, et al. The role of the EEG in Remifentanil
Development.
17
Remifentanil Therapeutic Ranges
18
Remifentanil DosingBased on Phase I PK/PD
19
Remifentanil Time Course
Egan, et al. The role of the EEG in Remifentanil
Development.
20
Relative Therapeutic Windows
Egan, et al. The role of the EEG in Remifentanil
Development.
21
Opioid Fingerprint, 1997
Egan, et al. The role of the EEG in Remifentanil
Development.
22
Remifentanil Fingerprint
Egan, et al. The role of the EEG in Remifentanil
Development.
23
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.

24
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
25
Three Compartment Model
26
Remifentanil vs. other opioids
100
10
Percent of peak plasma opioid concentration
fentanyl
1
sufentanil
alfentanil
remifentanil
0.1
0
120
240
360
480
600
Minutes since bolus injection
Minto et al, Anesthesiology, in press
27
Three Compartment Modelplus an Effect Site
28
Remifentanil vs. other opioids
100
sufentanil
80
fentanyl
60
Percent of peak effect site opioid concentration
40
alfentanil
20
remifentanil
0
0
2
4
6
8
10
Minutes since bolus injection
Minto et al, Anesthesiology, in press
29
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
alfentanil
20
sufentanil
0
remifentanil
120
fentanyl
90
alfentanil
Minutes required for a given percent decrease in
effect site concentration
60
50 decrease
sufentanil
30
remifentanil
0
300
fentanyl
240
alfentanil
180
80 decrease
120
sufentanil
60
remifentanil
0
0
120
240
360
480
600
Minutes since beginning of infusion
Shafer SL, ASA Refresher Course, Chapter 19, 1996
30
20 effect sitedecrement curves
60
fentanyl
40
Minutes required
alfentanil
20
sufentanil
remifentanil
0
0
120
240
360
480
600
Minutes since beginning of infusion
Shafer SL, ASA Refresher Course, Chapter 19, 1996
31
20 effect sitedecrement curves
60
fentanyl
40
Minutes required
alfentanil
20
sufentanil
remifentanil
0
0
120
240
360
480
600
Minutes since beginning of infusion
Shafer SL, ASA Refresher Course, Chapter 19, 1996
32
50 effect sitedecrement curves
Minutes required
Minutes since beginning of infusion
Shafer SL, ASA Refresher Course, Chapter 19, 1996
33
80 effect sitedecrement curves
Minutes required
Minutes since beginning of infusion
Shafer SL, ASA Refresher Course, Chapter 19, 1996
34
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
35
EC50 decreases with age

• EC50 is a measure ofbrain sensitivity
• Decreased EC50 means increased sensitivity
• Decreased EC50 with age also reported for
• fentanyl
• alfentanil
• sufentanil

36
t 1/2 ke0 increases with age

• t 1/2 ke0 is the time required for the brainto
  equilibrate withthe plasma
• an increase in t 1/2 ke0would be expected
  toresult in a slower onsetof drug effect

37
Age delays onset but does not affect peak
concentration
Minto et al, Anesthesiology, in press
38
Age Related Changes In Bolus Dose Parameters
Age (years)
20
50
80
Parameter
V
(liters)
5.5
5.1
4.3
1
t
k
(min)
0.94
1.32
2.20
1/2
e0
t
(min)
1.22
1.57
2.26
peak
Vd
(liters)
16.97
17.30
17.35
pe
-1
11.6
7.2
16.1
EC
(ng
ml
)

50
Bolus to peak at EC
(
m
g)
197
124
279
50
Minto et al, Anesthesiology, in press
39
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)
300
m
LBM
200
75kg
Bolus dose (
100
35kg
0
20
40
60
80
Age (years)
Minto et al, Anesthesiology, in press
40
Age Related Changes In Infusion Rate Parameters
Minto et al, Anesthesiology, in press
41
Infusion rates should be reduced by 2/3s 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)
40
m
LBM
30
75kg
20
Infusion rate (
10
35kg
0
20
40
60
80
Age (years)
Minto et al, Anesthesiology, in press
42
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
0
0
300
600
Infusion duration (minutes)
Minto et al, Anesthesiology, in press
43
Age effects on bolus dose
Minto et al, Anesthesiology, in press
44
Age effects on infusion rate
Minto et al, Anesthesiology, in press
45
Age affects variability in time to emergence
Minto et al, Anesthesiology, in press
46
Propofol/Alfentanil Interaction
400

• Adapted from Vuyk et al, Anesthesiology 838-22,
  1995
• Characterizes the concentrations for
• intubation
• maintenance
• on emergence
• Concentrations are 50 response level

Intubation
300
Maintenance
200
Alfentanil Concentration (ng/ml)
Emergence
100
0
0
2
4
6
8
10
Propofol Concentration (mg/ml)
47
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 831-5, 1995
48
Propofol/Opioid Technique
Stanski and Shafer Anesthesiology 831-5, 1995
Shafer SL, ASA Refresher Course, Chapter 19, 1996
49
Propofol/OpioidTime to Awakening
Alfentanil Technique
Remifentanil Technique
20
15
10
5
0
600

120
240
360
480
600
0
120
240
360
480
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996
50
Propofol/OpioidInfusion rates
Alfentanil Technique
Remifentanil Technique
400
300
Remifentanil (ng/kg/min)
Alfentanil (ng/kg/min)
200
Propofol (mg/kg/min)
Propofol (mg/kg/min)
100
0
600

120
240
360
480
600
0
120
240
360
480
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996
51
Propofol/OpioidPropofol Levels (mg/ml)
Alfentanil Technique
Remifentanil Technique
6
4
Maintenance
Maintenance
2
Emergence
Emergence
0
600

120
240
360
480
600
0
120
240
360
480
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996
52
Propofol/OpioidPercent Decrease on Emergence
Alfentanil Technique
Remifentanil Technique
100
75
Remifentanil
Propofol
50
Propofol
25
Alfentanil
0
600

120
240
360
480
600
0
120
240
360
480
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996
53
Propofol/Remifentanil TIVA

• Remifentanil
• 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

54
ULTIVA Dosing Guide