Quantification of In Vivo Metabolic Activity of CYP2D6 Genotypes and Alleles Through Population Pharmacokinetic Analysis of Vortioxetine

Abstract

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 the in vivo function of different CYP2D6 genotypes. Vortioxetine is metabolized to its major metabolite, Lu AA34443, primarily via CYP2D6. The aim of this study was to quantify the in vivo CYP2D6 activity of different CYP2D6 alleles 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 of CYP2D6*9, CYP2D6*10, CYP2D6*17, and CYP2D6*41 were 0.22, 0.37, 0.17, and 0.21, respectively. The activity of CYP2D6*10 was shown to be significantly greater than that of CYP2D6*17 (P = 0.01) and CYP2D6*41 (P = 0.02). These results warrant further discussion of current CYP2D6 genotype-phenotype classification systems particularly regarding decreased function alleles and the IM phenotype. Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of ~ 20% of all clinically used drugs. 1 The CYP2D6 gene is highly polymorphic and genetic variations may give rise to reduced, normal or increased activity of the CYP2D6 enzyme. Consequently, there are large interindividual differences in enzymatic activity, which, in turn, may cause differences

Evaluation of the CYP2D6 Haplotype Activity Scores Based on Metabolic Ratios of 4,700 Patients Treated With Three Different CYP2D6 Substrates

“…The results here obtained, which are based on a very large number of patients, support these data and argue that the decrease in metabolic activity encoded by the CYP2D6Decr alleles is indeed lower than 50% compared with the one of CYP2D6Norm . Related to the CYP2D6*41 allele, the here obtained results are concordant with previously published in vitro 11 and recent in vivo studies with CYP2D6 substrates other than those investigated here (i.e., tamoxifen 13 and vortioxetine,) 12 which also strongly suggest that the residual metabolic activity encoded by the CYP2D6*41 is very low. Moreover, the differences in metabolic activity in vivo between CYP2D6Nonf/Nonf and CYP2D6Nonf/*41 , as well as between CYP2D6Norm/Nonf and CYP2D6Norm/*41 , are quite modest.…”

Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone

“…Similar findings were observed by Brown et al who showed that systemic exposure of atomoxetine (AUC0-∞) of AS of 1 was not significantly different from that observed for subjects with an AS of 1.5 or 2 29 . In addition, Frederiksen et al 30 , demonstrated allele-specific metabolism of vortioxetine suggesting substantial differences among decreased function allele. Taken together, these findings raise awareness of the limitations and pitfalls of drug-agnostic genotype to phenotype translation methods.…”

Tri‐Allelic Haplotypes Determine and Differentiate Functionally Normal Allele CYP2D6*2 and Impaired Allele CYP2D6*41

“…A large venlafaxine drug monitoring study found the majority of CYP2D6*41/null allele carriers to be phenotypically in the range of PMs 21 . Further recent studies confirmed a strong impact of *41 and/or the IM phenotype also for vortioxetine, 22 risperidone, and aripiprazole, 23 as well as endoxifen 24 . Because of its high frequency and strong functional impact, reliable identification of CYP2D6*41 is important to avoid misclassification in clinical pharmacogenetics, and this requires knowledge of causative mutations.…”