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Dear Martine,
A population simulation study using GastroPlus™ could contribute to an understanding of the
drug-drug interaction effects over extended periods in a case like this.
Best regards,
Walt
Walt Woltosz
Chairman and CEO
Simulations Plus, Inc. (NASDAQ: SLP)
and Cognigen Corp, a wholly owned subsidiary of Simulations Plus
42505 10th Street West
Lancaster, CA 93534
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Dear Martine
You may find the following paper useful; the authors investigated the impact of victim drug
half-life and bioavailability and the study design on the level of drug-drug interaction using
simulation.
Zhao P, Ragueneau-Majlessi I, Zhang L, Strong JM, Reynolds KS, Levy RH, Thummel KE, and Huang S-M
(2009) Quantitative Evaluation of Pharmacokinetic Inhibition of CYP3A Substrates by Ketoconazole: A
Simulation Study. J Clin Pharmacol 49:351-359.
http://www.ncbi.nlm.nih.gov/pubmed/19246732
Regards
Masoud
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Hello Walt,
Thank you so much for bringing this option to the table. Will this study suffice for the FDA's DDI
interaction requirements? In other words, will we still have to do a clinical drug-drug interaction
study? I was thinking of study design in particular. For instance administration of the substrate
with a long-half life up to steady state (AUCtau comparisons as opposed to AUC0-inf) so that the
perpetrator won't be administered for a long period in normal volunteers.
Best regards,
Martine Allard
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Martine,
I cannot speak for the FDA, but there have been a few times when
simulation study results have reduced the need for clinical trials. I can
only guess that a study with the perpetrator administered for a shorter
period (to collect enough data to ensure the simulation results were
representative of that period) might provide confidence in simulation
study results extrapolated out to a longer period. If the model is
convincing, I think the FDA would want to take a hard look at it to see if
exposing subjects to both the drug and inhibitor for longer periods was
ethical and needed.
Best regards,
Walt
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Thank you Walt. Yes extrapolating the DDI impact via simulation. This one option.
The other is the do a multiple dose study so the substrate would reach steady state (AUCss) faster
than the entire time to collect AUC0-inf (the single dose approach. It would be a parallel design.
Another option is also to use a CYP3A4 inducer (rifampin) as the perpetrator drug so the substrate's
half life would be reduced as opposed to prolonged (with the CYP inhibitor). I do not know if
flipping the coin - using rifampin instead as the perpetrator - would suffice for regulatory
requirements.
I look forward to your comments.
Martine Allard
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Martine,
I would not hazard to guess whether a regulatory agency would go along
with any particular protocol. I think you have to develop your plan and
your substantiation for it and present it to the agency for their review.
I believe a strong argument could be made if you can show that an
alternative protocol is no less discriminatory than the original one, and
that it reduces unnecessary exposure of (healthy?) subjects to potential
adverse effects.
Best regards,
Walt
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Thank you Walt for your feedback.
I think we've got a study design down that limits exposure to a CYP3A4 inhibitor. A multiple dose
approach will give us an AUC to assess faster. Since AUCss is reached faster than the complete
AUC0-infinity with a molecule with a very long half life.
Best regards,
Martine Allard
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