Estimating the In Vivo Function of CYP2D6 Alleles through Population Pharmacokinetic Modeling of Brexpiprazole

Abstract

Accurate prediction of CYP2D6 phenotype from genotype information is important to support safe and efficacious pharmacotherapy with CYP2D6 substrates. To facilitate accurate CYP2D6 genotype–phenotype translation, there remains a need to investigate the enzyme activity associated with individual CYP2D6 alleles using large clinical data sets. This study aimed to quantify and compare the in vivo function of different CYP2D6 alleles through population pharmacokinetic (PopPK) modeling of brexpiprazole using data from 13 clinical studies. A PopPK model of brexpiprazole and its two metabolites, DM-3411 and DM-3412, was developed based on plasma concentration samples from 826 individuals. As the minor metabolite, DM-3412, is formed via CYP2D6, the metabolic ratio of DM-3412:brexpiprazole calculated from the PopPK parameter estimates was used as a surrogate measure of CYP2D6 activity. A CYP2D6 genotype–phenotype analysis based on 496 subjects showed that the CYP2D6*2 allele (n = 183) was associated with only 10% enzyme activity relative to the wild-type allele (CYP2D6*1) and a low enzyme activity was consistently observed across genotypes containing CYP2D6*2. Among the decreased function alleles, the following enzyme activities relative to CYP2D6*1 were estimated: 23% for CYP2D6*9 (n = 20), 32% for CYP2D6*10 (n = 62), 64% for CYP2D6*14 (n = 1), 4% for CYP2D6*17 (n = 37), 4% for CYP2D6*29 (n = 13), and 9% for CYP2D6*41 (n = 64). These findings imply that a lower functional value would more accurately reflect the in vivo function of many reduced function CYP2D6 alleles in the metabolism of brexpiprazole. The low enzyme activity observed for CYP2D6*2, which has also been reported by others, suggests that the allele exhibits substrate-specific enzyme activity.