Quantification ofIn VivoMetabolic Activity ofCYP2D6Genotypes and Alleles Through Population Pharmacokinetic Analysis of Vortioxetine

Assignment of CYP2D6 phenotype from genotype data can be challenging and despite efforts to standardize translation, there is currently no universally accepted method. To facilitate standardization, there remains a need to precisely quantify thein vivofunction of differentCYP2D6genotypes. Vortioxetine is metabolized to its major metabolite, Lu AA34443, primarily via CYP2D6. The aim of this study was to quantify thein vivoCYP2D6 activity of differentCYP2D6alleles and genotypes through population pharmacokinetic (PopPK) modeling of vortioxetine and Lu AA34443. Plasma concentration data of vortioxetine and Lu AA34443 from 1,140 subjects originating from 29 clinical pharmacology studies were pooled for the analysis. A joint PopPK model described the pharmacokinetics of vortioxetine and Lu AA34443 simultaneously and provided estimates of the CYP2D6-mediated metabolism for each subject. Subjects normally classified as CYP2D6 intermediate metabolizers (IMs) showed different levels of CYP2D6 activity with carriers of one fully functional allele and one null function allele having 77% higher CYP2D6 activity compared with carriers of two decreased function alleles (P < 0.0001). The decreased function alleles were associated with different levels of reduction of CYP2D6 activity. Fixing the activity of fully functional alleles to 1.0, the relative activities ofCYP2D6*9,CYP2D6*10,CYP2D6*17, andCYP2D6*41were 0.22, 0.37, 0.17, and 0.21, respectively. The activity ofCYP2D6*10was shown to be significantly greater than that ofCYP2D6*17(P = 0.01) andCYP2D6*41(P = 0.02). These results warrant further discussion of currentCYP2D6genotype-phenotype classification systems particularly regarding decreased function alleles and the IM phenotype.