HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Sign In to gain access to subscriptions and/or personal tools.

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Williams, J. A. Articles by Cook, J. Search for Related Content PubMed PubMed Citation Articles by Williams, J. A. Articles by Cook, J. Social Bookmarking                         What's this?

So Many Studies, Too Few Subjects: Establishing Functional Relevance of Genetic Polymorphisms on Pharmacokinetics

From Pharmacokinetics, Dynamics and Metabolism (Dr Williams), Molecular Profiling (Dr Johnson), Worldwide Safety Sciences (Dr Paulauskis), Clinical Pharmacokinetics and Pharmacodynamics (Dr Cook), Pfizer Global Research and Development, Ann Arbor, Michigan.

Based on current literature, greater clarity in defining the magnitude of polymorphism effects on pharmacokinetics can be achieved by addressing key components of study design, including adequate subject numbers per study group. Convincing evidence of functional relevance exists for polymorphisms in genes such as CYP2D6 and UGT1A1, whereas the published evidence for similar effects for CYP3A5, OATP1B1, and ABCB1 is still emerging or equivocal. Polymorphism-associated differences in pharmacokinetic parameters were simulated to incorporate (1) the ratio of group mean parameter values for homozygous wild-type subjects versus homozygous variants, (2) pharmacokinetic variability, and (3) sample size needed to achieve 80% power, assuming 69% coefficient of variation. Subject selection by genotype and choice of probe substrate are also considered. Simulation results and literature examples are incorporated to define key recommendations for future investigations. This will allow for more definitive statements in publications regarding genotype influence on pharmacokinetics.

Key Words: Polymorphisms • pharmacokinetics • pharmacogenetics • drug disposition • drug-metabolizing enzymes • drug transporters

Address for reprints: J. Andrew Williams, Pfizer Global Research and Development, Department of Pharmacokinetics, Dynamics and Metabolism, 2800 Plymouth Road, Ann Arbor, MI, 48105.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				G. L. Dickinson, S. Rezaee, N. J. Proctor, M. S. Lennard, G. T. Tucker, and A. Rostami-Hodjegan 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 J. Clin. Pharmacol., February 1, 2007; 47(2): 175 - 186. [Abstract] [Full Text] [PDF]