Pharmacokinetics and Pharmacodynamics in Anesthetic Drug Development

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Pharmacokinetics and Pharmacodynamics in
Anesthetic Drug Development
Steven L. Shafer, M.D. Palo Alto VA Health Care
System Stanford University School of
Medicine University of California at San Francisco
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Please Fasten Safety BeltsPrior to Take Off
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Pharmacokinetics Volume of Distribution
4
Pharmacokinetics Clearance
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Pharmacokinetics Half-Life

• The time required for drug concentrations to
  decrease by 50.

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Comparative Pharmacokinetics of Duzitol
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Three Compartment Model
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Three Compartment Model
Rapid
Intermediate
Slow
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Opioid Half-Lives (minutes)
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Opioid Pharmacokinetics
100
10
Percent of peak plasma opioid concentration
fentanyl
1
sufentanil
alfentanil
0.1
0
120
240
360
480
600
Minutes since bolus injection
13
Context-Sensitive Half-Time
120
fentanyl
90
alfentanil
Minutes required
60
sufentanil
30
0
0
120
240
360
480
600
Minutes since beginning of infusion
14
20 Decrement Time
60
fentanyl
40
Minutes required
alfentanil
20
sufentanil
0
0
120
240
360
480
600
Minutes since beginning of infusion
15
80 Decrement Time
300
fentanyl
240
alfentanil
180
Minutes required
120
sufentanil
60
0
0
120
240
360
480
600
Minutes since beginning of infusion
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Awake EEG
Gregg K, Varvel JR, Shafer SL. J Pharmacokinet
Biopharm 20, 611-635, 1992
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Profound Opioid EEG Effect
Gregg K, Varvel JR, Shafer SL. J Pharmacokinet
Biopharm 20, 611-635, 1992
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EEG Time Course with Fentanyl
Scott J, Ponganis KV, Stanski DR. Anesthesiology
62234-241, 1985
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EEG Time Course with Alfentanil
Scott J, Ponganis KV, Stanski DR. Anesthesiology
62234-241, 1985
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Three Compartment Modelplus an Effect Site
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Effect Site Concentrations
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Valid Benefits of Alfentanil

• Bolus injections where quick onset is desired.
• Long infusions where rapid recovery is desired.
• For everything else, sufentanil gives faster
  recovery.

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Sufentanil vs. Fentanyl

• Higher lipid solubility
• Shorter beta elimination half-life
• More rapid induction
• Improved hemodynamic stability
• More rapid recovery

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Comparison of sufentanil - O2 and Fentanyl - O2
for coronary artery surgery
de Lange S, Boscoe MJ, Stanley TH, Pace N.
Anesthesiology 56112-118, 1982
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Relative PotencyFentanyl vs. Sufentanil
Sufentanil
Fentanyl
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Sufentanil vs. Fentanyl

• Higher lipid solubility irrelevant
• Shorter beta elimination half-life incorrect
• More rapid induction incorrect
• Improved hemodynamic stability never shown
• More rapid recovery yes, despite its
• long half-life!

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What happens when companies get the PK/PD wrong?
Case reportThe Introduction of Versed
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Midazolam and Diazepam Clinical Pharmacology
(as originally introduced into clinical practice)
Elimination
Equipotent
Onset
Half-Life
Duration
Doses
Diazepam
"slow"
40 hr
"long"
10 mg
Midazolam
"fast"
4 hr
"short"
5 mg
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Result of initial dosing guidelines

• 1600 adverse reactions and 86 deaths associated
  with midazolam in the first 5 years after its
  introduction in the United States.
• Department of Health and Human Services, Office
  of Epidemiology and Biostatistics, Center for
  Drug Evaluation and Research, Data Retrieval Unit
  HFD-737, June 27, 1989
• Nearly all were associated with midazolam for
  sedation during endoscopy

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FDAS REGULATION OF THE NEW DRUG
VERSED
HEARINGS
BEFORE A
SUBCOMMITTEE OF THE
COMMITTEE ON
GOVERNMENT OPERATIONS
HOUSE OF REPRESENTATIVES
ONE HUNDREDTH CONGRESS
SECOND SESSION
MAY 5 AND 10, 1988
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Midazolam Sedation for Endoscopy
Adapted from Bell, J Clin Pharmacol 1987
Feb23(2)241-3
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Midazolam-Opioid Interactions(young volunteers)
Adapted from Kissen et al, Anesth Analg 7265-69,
1990
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EEG Effects of Midazolam
Adapted from Bührer, CPT 48555-567, 1990
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Revised Midazolam Comparative Pharmacology
Plasma-Effect Site
Equilibration Half-Life
Potency
range (average)
range (mean)
1-2.4 min
406-1256 ng/ml
Diazepam
(1.6 min)
(958 ng/ml)
1.6-6.8 min
94-385 ng/ml
Midazolam
(4.8 min)
(190 ng/ml)
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Drug Interaction Model
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RemifentanilA Better Approach

• 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)

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Alfentanil Clinical Concentration vs Response
Ausems ME, Hug CC, Stanski DR, Burm AGL
Anesthesiology 65362-373, 1986
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Alfentanil Concentration-Response Relationships
Egan, et al. The role of the EEG in Remifentanil
Development.
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Opioid Therapeutic Ranges
Billard V, Shafer SL. Control and Automation in
Anesthesia. 1995, Springer
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Fentanyl, Alfentanil, Sufentanil EEG
Billard V, Shafer SL. Control and Automation in
Anesthesia. 1995, Springer
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EEG Response as a fraction of IC50
Billard V, Shafer SL. Control and Automation in
Anesthesia. 1995, Springer
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EEG vs Therapeutic Ranges
Billard V, Shafer SL. Control and Automation in
Anesthesia. 1995, Springer
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EEG vs Opioid Therapeutic Ranges
Billard V, Shafer SL. Control and Automation in
Anesthesia. 1995, Springer
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EEG Time Course with Remifentanil
Egan, et al. Anesthesiology 84881-833, 1996
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Remifentanil Therapeutic Ranges
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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
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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, 8610-23, 1997
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50 effect sitedecrement curves
Minutes required
Minutes since beginning of infusion
Shafer SL, ASA Refresher Course, Chapter 19, 1996
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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, 8610-23, 1997
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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

Minto et al, Anesthesiology, 8610-23, 1997
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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

Minto et al, Anesthesiology, 8610-23, 1997
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Age delays onset but does not affect peak
concentration
Minto et al, Anesthesiology, 8624-33, 1997
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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, 8624-33, 1997
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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, 8624-33, 1997
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Remifentanil DosingBased on Phase I PK/PD
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Remifentanil Fingerprint
Egan, et al. The role of the EEG in Remifentanil
Development.
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ULTIVA Dosing Guide
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Result of Using Modeling andSimulation for
Remifentanil

• Patent to FDA approval in 4 years.
• Glaxo published the experience at several
  meetings, and claimed a savings of tens of
  millions of dollars in drug development.
• Accurately assessed clinical profile
• Package insert has not required modification
  since approval in 1996

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Propofol for ICU Sedation

• Acknowledgements
• Dr. Juliana Barr
• Katie Zomorodi
• David Goodale

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Modified Ramsay Sedation Scale
0 - paralyzed 1 - fully awake 2 - drowsy, awakens
spontaneously 3 - asleep, responds to verbal
command 4 - responds to shoulder tap with loud
command 5 - responds to facial tap with loud
command 6 - unresponsive to facial tap with loud
command
Ramsay et al, BMJ 1974 2656-659
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Study Design
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Original Pharmacokinetic Model
Best 10 MDAPE (infusion only)
Worst 60MDAPE (infusion only)
Plasma Propofol Concentration (mg/ml)
Hours Since Initial Dose
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Propofol ICU Pharmacokinetics
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Optimal Pharmacokinetic Model
Best 13 MDAPE
Worst 70MDAPE
Plasma Propofol Concentration (mg/ml)
Hours Since Initial Dose
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Prospective Pharmacokinetic Test
Retrospective MDAPE24
Prospective MDAPE29
Performance Error
Hours since initial dose
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Probability Pharmacodynamics(NONMEM analysis)
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Propofol Pharmacodynamics
1.00
gt Level 2
gt Level 4
Light
0.75
Probability of Sedation Score
0.50
0.25
Deep
0.00
0
1
2
3
m
Plasma Propofol Concentration (
g/ml)
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Propofol Dosing in the ICU
For 25, 50, and 75 mg/kg/min
2.5

Women
Men
2.0
75
1.5
50
1.0
Small
25
0.5
0.0
2.5
2.0
Plasma Propofol Concentration (mg/ml)
1.5
Big
1.0
0.5
0.0
2.5
2.0
1.5
Obese
1.0
0.5
0.0
1
10
100
1000
10000
1
10
100
1000
10000
Minutes Since Beginning of Infusion
Based on Lean Body Mass correction for gender
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ICU decrement times
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The FDA perspective
Target plasma concentration
1.00
Recovery after
10 day infusion
10 hour infusion
0.75
1 hour infusion
Awakening
Plasma propofol concentration
0.50
0.25
0.00
0
20
40
60
80
Minutes after end of infusion
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Propofol Package Insert
DIPRIVAN Injectable Emulsion should be
individualized according to the patient's
condition and response, blood lipid profile, and
vital signs. (See PRECAUTIONS --ICU Sedation.)
For intubated, mechanically ventilated adult
patients, Intensive Care Unit (ICU) sedation
should be initiated slowly with a continuous
infusion in order to titrate to desired clinical
effect and minimize hypotension. When indicated,
initiation of sedation should begin at 5
µg/kg/min (0.3 mg/kg/h). The infusion rate should
be increased by increments of 5 to 10 µg/kg/min
(0.3 to 0.6 mg/kg/h) until the desired level of
sedation is achieved. A minimum period of 5
minutes between adjustments should be allowed for
onset of peak drug effect. Most adult patients
require maintenance rates of 5 to 50 µg/kg/min
(0.3 to 3 mg/kg/h) or higher. Dosages of DIPRIVAN
Injectable Emulsion should be reduced in patients
who have received large dosages of narcotics.
Conversely, the DIPRIVAN Injectable Emulsion
dosage requirement may be reduced by adequate
management of pain with analgesic agents. As with
other sedative medications, there is interpatient
variability in dosage requirements, and these
requirements may change with time. (See dosage
guide.)
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Propofol for MAC Sedation

• Acknowledgements
• Paul White
• David Goodale

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Initiation of MAC Sedation   For initiation of
MAC sedation, either an infusion or a slow
injection method may be utilized while closely
monitoring cardiorespiratory function. With the
infusion method, sedation may be initiated by
infusing DIPRIVAN Injectable Emulsion at 100 to
150 µg/kg/min (6 to 9 mg/kg/h) for a period of 3
to 5 minutes and titrating to the desired
clinical effect while closely monitoring
respiratory function. With the slow injection
method for initiation, patients will require
approximately 0.5 mg/kg administered over 3 to 5
minutes and titrated to clinical responses. When
DIPRIVAN Injectable Emulsion is administered
slowly over 3 to 5 minutes, most patients will be
adequately sedated, and the peak drug effect can
be achieved while minimizing undesirable
cardiorespiratory effects occurring at high
plasma levels. In the elderly, debilitated, or
ASA III/IV patients, rapid (single or repeated)
bolus dose administration should not be used for
MAC sedation. (See WARNINGS .) The rate of
administration should be over 3-5 minutes and the
dosage of DIPRIVAN Injectable Emulsion should be
reduced to approximately 80 of the usual adult
dosage in these patients according to their
condition, responses, and changes in vital signs.
(See DOSAGE AND ADMINISTRATION .) Maintenance of
MAC Sedation   For maintenance of sedation, a
variable rate infusion method is preferable over
an intermittent bolus dose method. With the
variable rate infusion method, patients will
generally require maintenance rates of 25 to 75
µg/kg/min (1.5 to 4.5 mg/kg/h) during the first
10 to 15 minutes of sedation maintenance.
Infusion rates should subsequently be decreased
over time to 25 to 50 µg/kg/min and adjusted to
clinical responses. In titrating to clinical
effect, allow approximately 2 minutes for onset
of peak drug effect.
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Propofol/opioid vs Isoflurane/opioid
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Propofol/opioid vs Isoflurane/opioid