Incorporating In Vitro Information on Drug Metabolism Into Clinical Trial Simulations to Assess the Effect of CYP2D6 Polymorphism on Pharmacokinetics and Pharmacodynamics: Dextromethorphan as a Model Application

In vitro–in vivo extrapolation of clearance, embedded in a clinical trial simulation, was used to investigate differences in the pharmacokinetics and pharmacodynamics of dextromethorphan between CYP2D6 poor and extensive metabolizer phenotypes. Information on the genetic variation of CYP2D6, as well...

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Bibliographic Details
Published in:Journal of clinical pharmacology 2007-02, Vol.47 (2), p.175-186
Main Authors: Dickinson, Gemma L., Rezaee, Saeed, Proctor, Nicholas J., Lennard, Martin S., Tucker, Geoffrey T., Rostami-Hodjegan, Amin
Format: Article
Language:English
Subjects:
Antitussive Agents - blood
Antitussive Agents - pharmacokinetics
Antitussive Agents - pharmacology
clinical trial simulation
Clinical Trials as Topic
Computer Simulation
Cough - drug therapy
Cytochrome P-450 CYP2D6 - genetics
Cytochrome P-450 CYP2D6 - metabolism
cytochrome P450
Dextromethorphan
Dextromethorphan - blood
Dextromethorphan - pharmacokinetics
Dextromethorphan - pharmacology
Dextrorphan - blood
Drug metabolism
Genetic polymorphisms
in silico
Models, Biological
pharmacogenetics
Pharmacokinetics
Physiological aspects
Polymorphic drug metabolism
Polymorphism, Genetic
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Summary:In vitro–in vivo extrapolation of clearance, embedded in a clinical trial simulation, was used to investigate differences in the pharmacokinetics and pharmacodynamics of dextromethorphan between CYP2D6 poor and extensive metabolizer phenotypes. Information on the genetic variation of CYP2D6, as well as the in vitro metabolism and pharmacodynamics of dextromethorphan and its active metabolite dextrorphan, was integrated to assess the power of studies to detect differences between phenotypes. Whereas 6 subjects of each phenotype were adequate to achieve 80% power in showing pharmacokinetic differences, the power required to detect a difference in antitussive response was less than 80% with 500 subjects in each study arm. Combining in vitro–in vivo extrapolation with a clinical trial simulation is useful in assessing different elements of study design and could be used a priori to avoid inconclusive pharmacogenetic studies.
ISSN:0091-2700
1552-4604
DOI:10.1177/0091270006294279