title: 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.
abstract: 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.
authors.affiliation: Academic Unit of Clinical Pharmacology, School of Medicine, University of Sheffield, M-floor, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Dickinson
authors.forename: Saeed
authors.initials: S
authors.lastname: Rezaee
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Proctor
authors.forename: Martin S
authors.initials: MS
authors.lastname: Lennard
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Tucker
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
mesh_terms: D000996:Antitussive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D003371:Cough / Q000188:drug therapy*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D003915:Dextromethorphan / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003917:Dextrorphan / Q000097:blood; D008954:Models, Biological; D011110:Polymorphism, Genetic
chemical_list: D000996:Antitussive Agents; D003917:Dextrorphan; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6