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DRUG METABOLISM

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

Gemma L. Dickinson, BSc, Saeed Rezaee, PharmD, PhD, Nicholas J. Proctor, PhD, Martin S. Lennard, PhD, Geoffrey T. Tucker, PhD and Amin Rostami-Hodjegan, PharmD, PhD, FCP

From the Academic Unit of Clinical Pharmacology, School of Medicine, University of Sheffield, Sheffield, UK (Ms Dickinson, Dr Proctor, Dr Lennard, Professor Tucker, Dr Rostami-Hodjegan); the Department of Pharmaceutics, Faculty of Pharmacy, Ahwaz University of Medical Sciences, Iran (Dr Rezaee); and Simcyp Limited, Sheffield, UK (Professor Tucker, Dr Rostami-Hodjegan).

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.

Key Words: Polymorphic drug metabolism • pharmacogenetics • cytochrome P450 • in silico • clinical trial simulation

Address for reprints: Address for correspondence: Dr Amin Rostami-Hodjegan, Academic Unit of Clinical Pharmacology, University of Sheffield, M-floor, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK; e-mail: a.rostami{at}sheffield.ac.uk.


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