Towards Target Controlled Drug Delivery

1
Towards Target ControlledDrug Delivery

• Steven L. Shafer, M.D.
• Professor of Anesthesia, Stanford University
• Adjunct Professor of Biopharmaceutical Sciences,
  UCSF

2
TCI Generations

• First Generation
• Targets the plasma concentration
• Diprifusor
• Second Generation
• Targets the effect site concentration
• STANPUMP, RUGLOOP, Fresenius
• Third Generation
• Targets the drug effect
• STANPUMP (Open Loop, Bayesian)
• RUGLOOP (Closed Loop, Bayesian)
• IVAC Titrator
• Schwilden System (Bonn, Erlangen)

3
First Generation
First TCI system foranesthetics (Schwilden et al)
First TCI system forNMB (Westenskow et al)
Courtesy of Talmage Egan, MD
4
TCI Surfing USA Not

• Clinical anesthesia involved constant titration
  to effect
• The if you try to understand the dose vs.
  response relationship in real time, you discover
  that
• The wave changes during the ride to shore
• As soon as you leave the wave, it changes

• It is far easier to understand the concentration
  vs. response relationship during anesthesia
  because
• It doesnt change over time
• It doesnt change with dosing history

5
TCI Worldwide

• Over 280 peer-reviewed articles in Medline as of
  last night
• Over 50 articles on the Diprifusor alone
• Over 13 million anesthetics
• Approved everyway except in North America

6
Why isnt TCI available in the US?

• A single individual at the Food and Drug
  Administration has resolutely blocked
  introduction of TCI into the United States.
• This individual wrote in an obscure article in
  the early 1990s
• No utility for TCI in anesthesia practice.
• His view has never wavered at the FDA.
• In a paper submitted for publication 5 years ago,
  this individual demonstrated total ignorance of
  the enormous history of TCI research, as well as
  the fundamental PK concepts
• The Diprifusor application has languished in the
  FDA for 8 years.

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Accuracy of TCI

• 20 typical error with right PK

Glass et al. Anesthesia, 6th edition, Chapter 12
8
Second Generation
Stanpump (Shafer et al)
Courtesy of Talmage Egan, MD
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Second Generation TCI

• The Plasma is NOT the site of drug effect!

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Awake EEG
Gregg et al. J Pharmacokinet Biopharm 20,
611-635, 1992
11
Profound Opioid EEG Effect
Gregg et al,. J Pharmacokinet Biopharm 20,
611-635, 1992
12
EEG Time Course with Fentanyl
30
0
Arterial
5
Level
EEG
20
10
Fentanyl (ng/ml)
Spectral Edge (Hz)
10
15
20
Infusion
0
0
5
10
15
20
25
Time (min)
Scott et al, Anesthesiology 62234-241, 1985
13
EEG Time Course with Alfentanil
1500
0
Arterial
5
Level
1000
10
EEG
Alfentanil (ng/ml)
15
Spectral Edge (Hz)
500
20
25
Infusion
0
0
5
10
15
20
25
Time (min)
Scott et al, Anesthesiology 62234-241, 1985
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Three Compartment Modelplus an Effect Site
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Titrating the Plasma
Shafer and Gregg. J Pharmacokinet Biopharm
20147-169, 1992
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Performs poorly at the site of drug effect!
Shafer and Gregg. J Pharmacokinet Biopharm
20147-169, 1992
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Targeting the Effect Site
Shafer and Gregg. J Pharmacokinet Biopharm
20147-169, 1992
18
Drugs With Rapid Equilibration May Perform
Inadequately with Plasma Control
Shafer and Gregg. J Pharmacokinet Biopharm
20147-169, 1992
19
Effect Site Control Works Very Well for Drugs
With Rapid Equilibration
Shafer and Gregg. J Pharmacokinet Biopharm
20147-169, 1992
20
Plasma Control of Propofol
Struys et al, Anesthesiology, 92399-406, 2000
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Effect Site Control of Propofol
Struys et al, Anesthesiology, 92399-406, 2000
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Third Generation
RUGLOOP (De Smet and Struys)
Courtesy of Talmage Egan, MD
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Closed Loop Control of Propofol
closed-loop control classic-control
BIS
Systolic
Heart Rate
Struys et al, Anesthesiology. 956-17, 2001
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Outcome Measures with Closed Loop
Struys et al, Anesthesiology. 956-17, 2001
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Propofol Sedation in the ICU
Barr et al, Anesthesiology. 95 324-33, 2001
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Propofol ICU Pharmacokinetics
Barr et al, Anesthesiology. 95 324-33, 2001
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Optimal Propofol ICU PK Model
Best 13 MDAPE
Worst 70MDAPE
Plasma Propofol Concentration (mg/ml)
Hours Since Initial Dose
Barr et al, Anesthesiology. 95 324-33, 2001
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Midazolam TCI in the ICU
Zomorodi et al, Anesthesiology 891418-1429, 1998
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Midazolam TCI in the ICU
Somma et al, Anesthesiology 891430-1443, 1998
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TCI in Clinical Trial Programs

• Abbott Dexmedetomidine
• Zeneca Propofol in the ICU
• Roche Midazolam in the ICU
• Durect Sufentanil trials

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Hierarchical Model of Drug Interaction
AmbientStimuli
Afferent Stimuli
Pain projection
to cortex
Pain
Pain
Bouillon et al, Anesthesiology in press
32
Propofol-Remifentanil InteractionHierarchical
Model, Laryngoscopy
Bouillon et al, Anesthesiology (in press)
33
D. Beattie, et al, EuroSiva 2002
34
D. Beattie, et al, EuroSiva 2002
35
Available TCI Software

• Diprifusor (Commercially available)
• Fresenius (Recently approved)
• Propofol effect site
• Remifentanil
• Sufentanil
• RUGLOOP (Windows)
• http//users.skynet.be/fa491447/index.html
• STANPUMP, STELPUMP, IVA-SIM (DOS)
• http//anesthesia.stanford.edu/pkpd

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How do you want to fly ???
Courtesy of Talmage Egan, MD