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.

CYP2B6 Pharmacogenetics–Based In Vitro–In Vivo Extrapolation of Efavirenz Clearance by Physiologically Based Pharmacokinetic Modeling

“…It appears that expressed CYP2B6 protein may be superior to HLMs in IVIVE, especially for the prediction in individuals with reduced-function alleles. However, variable successes were obtained using data from expressed cytochrome P450s, e.g., CYP2C9 (Dickinson et al, 2007a;Kusama et al, 2009), CYP2D6 (Dickinson et al, 2007b), and CYP2B6 (Siccardi et al, 2012). Therefore, the selection of a relevant in vitro system may be dependent on the specific cytochrome P450 isoform and variant allele studied.…”

Evaluation of the relationship between plasma concentrations of en- and zuclomiphene and induction of ovulation in anovulatory women being treated with clomiphene citrate

“…Whether CYP2D6 genotype is a determinant of response to CC is unknown. The propagation of genetic polymorphism in metabolism to pharmacologic response requires knowledge of the relative activity of metabolites, the relative concentrations of parent and metabolite in the systemic circulation, and extraction ratio of compound in liver, as well as a number of other parameters (34). None of these data are known for CC.…”

Prediction of the Effects of Genetic Polymorphism on the Pharmacokinetics of CYP2C9 Substrates from In Vitro Data

“…The changes in enzymatic activities and expression levels of CYP2C9 variants (*2 and *3) were incorporated in their prediction, but this method was not extended to other CYP2C9 substrates. Recently, in some reports, when estimating the impact of the change in the metabolic activity of specific enzyme caused by genetic polymorphisms or drug interaction on the pharmacokinetics of substrate drugs, the contribution of specific CYP isozyme to the overall clearance of drugs was considered (30,31), but this method has not been systematically applied to the prediction of the effect of genetic polymorphisms of CYP2C9 on the clinical pharmacokinetics of various drugs. Therefore, we proposed a general theoretical method for the prediction of the effects of CYP2C9 polymorphisms on the pharmacokinetics of several kinds of substrate drugs from in vitro data by incorporating not only the changes in enzymatic activities and expression levels, but also the contribution of CYP2C9 to the overall clearance.…”

“…For example, the oral clearances of warfarin in *1/*1, *2/*2, and *3/*3 subjects varies considerably (39.6, 12.8, 3.7 L/h) (16), but those of losartan (64, 57, 39 L/h) (17) and diclofenac (20,30,23 L/h) (18) do not show large differences among subjects with mutant alleles. These kinds of substrate-specific effects of CYP2C9 mutations on the pharmacokinetics are attributed to differences in the contribution of CYP2C9 to the overall clearance of drugs and differences in the decrease in the intrinsic clearances by mutated enzymes.…”