I am looking for an appropriate design and modeling strategy for inhibition of
levodopa-induced dyskinesia (LID) in a rat model of Parkinsons disease.
Dyskinesia (AIM) is scored categorically 0,1,2,3 or 4. The two active drugs by
them selves only have a minor maximum response in the model (reversal of AIMS),
but displays synergy when combined.
My intended PKPD study design is maintaining a relative constant dyskinesia
level with levodopa, and combine three doses each (low, medium, high) of the
inhibitory drugs A and B, in a total of 9 treatments in addition to a levodopa
baseline study.
With respect to the modeling strategy, my intention is to establish a baseline
model for levodopa-induced dyskinesia. Do you have suggestions/literature
references for models that could be applied to analyse the synergistic
inhibitory responses of drug A and B?
Best regards,
Mads
Dual inhibitor synergy model
Dear Mads
If the purpose of your study is to understand the time course of effects of
drugs on various scores of PD then maintaining relatively constant score levels
will most likely yield low information in your design.
You should aim for finding a design where the score is most sensitive to your
study variable (dose, drug, drug combination, time etc). Generally designs
that allow you to learn about PKPD are not good for maintaining stable patient
outcomes. You may wish to consider a design that weights the desire for a good
therapeutic outcome against the ability to learn about the system.
Regards
Steve
--
Professor Stephen
http://pharmacy.otago.ac.nz/our-people/academic-staff/stephen-duffull
Chair of Clinical Pharmacy
School of Pharmacy
University of Otago
PO Box 56 Dunedin
New Zealand
E: [email protected]<mailto:[email protected]>
P: +64 3 479 5044
F: +64 3 479 7034
Design software: http://www.winpopt.com/
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Mads Kreilgaard
Sent: Wednesday, 7 March 2012 10:03 a.m.
To: [email protected]
Subject: [NMusers] Dual inhibitor synergy model
I am looking for an appropriate design and modeling strategy for inhibition of
levodopa-induced dyskinesia (LID) in a rat model of Parkinsons disease.
Dyskinesia (AIM) is scored categorically 0,1,2,3 or 4. The two active drugs by
them selves only have a minor maximum response in the model (reversal of AIMS),
but displays synergy when combined.
My intended PKPD study design is maintaining a relative constant dyskinesia
level with levodopa, and combine three doses each (low, medium, high) of the
inhibitory drugs A and B, in a total of 9 treatments in addition to a levodopa
baseline study.
With respect to the modeling strategy, my intention is to establish a baseline
model for levodopa-induced dyskinesia. Do you have suggestions/literature
references for models that could be applied to analyse the synergistic
inhibitory responses of drug A and B?
Best regards,
Mads
Mads,
You might start with some of the work of Chou and Talalay. Here is a
recent paper on study design
Drug Combination Studies and Their Synergy Quantification Using the
Chou-Talalay Method Ting-Chao Chou
In Cancer Res January 15, 2010 70; 440
It is based on some pretty old work on quantifying synergy. Bottom line,
it is really, really hard, requiring nearly a full-grid of doses (e.g.,
16 doses, a 4x4 matrix of doses). Stella Machado also did some work,
slightly different synergy model, here is an example.
Analysis of Antimalarial Synergy between Bestatin and Endoprotease
Inhibitors Using Statistical Response-Surface Modelling by Clare S
Gavigan, Stella G Machado, John P Dalton, Angus Bell
Antimicrobial Agents and Chemotherapy (2001)
Volume: 45, Issue: 11, Publisher: American Society for Microbiology,
Pages: 3175-3181
Mark Sale MD
President, Next Level Solutions, LLC
www.NextLevelSolns.com
919-846-9185
A carbon-neutral company
See our real time solar energy production at:
http://enlighten.enphaseenergy.com/public/systems/aSDz2458
Quoted reply history
-------- Original Message --------
Subject: [NMusers] Dual inhibitor synergy model
From: Mads Kreilgaard <[email protected]>
Date: Tue, March 06, 2012 4:02 pm
To: "[email protected]" <[email protected]>
I am looking for an appropriate design and modeling strategy for
inhibition of levodopa-induced dyskinesia (LID) in a rat model of
Parkinsons disease. Dyskinesia (AIM) is scored categorically 0,1,2,3 or
4. The two active drugs by them selves only have a minor maximum
response in the model (reversal of AIMS), but displays synergy when
combined. My intended PKPD study design is maintaining a relative
constant dyskinesia level with levodopa, and combine three doses each
(low, medium, high) of the inhibitory drugs A and B, in a total of 9
treatments in addition to a levodopa baseline study.
With respect to the modeling strategy, my intention is to establish a
baseline model for levodopa-induced dyskinesia. Do you have
suggestions/literature references for models that could be applied to
analyse the synergistic inhibitory responses of drug A and B?
Best regards,
Mads
Thanks a lot for your very useful suggestions and references.
Best regards,
Mads
___________________________________
Mads Kreilgaard (Ph.D.)
Associate Professor
University of Copenhagen
Faculty of Health and Medical Sciences
Dept Drug Design & Pharmacology
Universitetsparken 2
DK-2100 Copenhagen
Denmark
Quoted reply history
________________________________________
From: [email protected] [[email protected]] on behalf of
Mark Sale - Next Level Solutions [[email protected]]
Sent: Tuesday, March 06, 2012 10:49 PM
To: [email protected]
Subject: RE: [NMusers] Dual inhibitor synergy model
Mads,
You might start with some of the work of Chou and Talalay. Here is a
recent paper on study design
Drug Combination Studies and Their Synergy Quantification Using the
Chou-Talalay Method Ting-Chao Chou
In Cancer Res January 15, 2010 70; 440
It is based on some pretty old work on quantifying synergy. Bottom line,
it is really, really hard, requiring nearly a full-grid of doses (e.g.,
16 doses, a 4x4 matrix of doses). Stella Machado also did some work,
slightly different synergy model, here is an example.
Analysis of Antimalarial Synergy between Bestatin and Endoprotease
Inhibitors Using Statistical Response-Surface Modelling by Clare S
Gavigan, Stella G Machado, John P Dalton, Angus Bell
Antimicrobial Agents and Chemotherapy (2001)
Volume: 45, Issue: 11, Publisher: American Society for Microbiology,
Pages: 3175-3181
Mark Sale MD
President, Next Level Solutions, LLC
www.NextLevelSolns.com
919-846-9185
A carbon-neutral company
See our real time solar energy production at:
http://enlighten.enphaseenergy.com/public/systems/aSDz2458
-------- Original Message --------
Subject: [NMusers] Dual inhibitor synergy model
From: Mads Kreilgaard <[email protected]>
Date: Tue, March 06, 2012 4:02 pm
To: "[email protected]" <[email protected]>
I am looking for an appropriate design and modeling strategy for
inhibition of levodopa-induced dyskinesia (LID) in a rat model of
Parkinsons disease. Dyskinesia (AIM) is scored categorically 0,1,2,3 or
4. The two active drugs by them selves only have a minor maximum
response in the model (reversal of AIMS), but displays synergy when
combined. My intended PKPD study design is maintaining a relative
constant dyskinesia level with levodopa, and combine three doses each
(low, medium, high) of the inhibitory drugs A and B, in a total of 9
treatments in addition to a levodopa baseline study.
With respect to the modeling strategy, my intention is to establish a
baseline model for levodopa-induced dyskinesia. Do you have
suggestions/literature references for models that could be applied to
analyse the synergistic inhibitory responses of drug A and B?
Best regards,
Mads