Association Between CYP2D6 Metabolizer Status and Vortioxetine Exposure and Treatment Switching: A Retrospective, Naturalistic Cohort Study Using Therapeutic Drug Monitoring Data From 640 Patients.

Purpose: The antidepressant vortioxetine is mainly metabolized by the polymorphic enzyme CYP2D6. The aim of this study was to investigate the absolute serum concentrations of vortioxetine and frequency of switching to an alternative antidepressant in relation to CYP2D6 genotype in a naturalistic patient population.

Methods: The analyses included data from 640 CYP2D6 -genotyped patients treated with vortioxetine from a Norwegian therapeutic drug monitoring database. Serum concentration of vortioxetine was determined using ultrahigh-performance liquid chromatography-high-resolution mass spectrometry, whereas longitudinal reviews of therapeutic drug monitoring profiles were performed to identify cases of patients switching from vortioxetine to an alternative antidepressant.

Results: Compared with CYP2D6 normal metabolizers (n = 342), the median vortioxetine serum concentration (ng/mL) was 2.1-fold ( P < 0.001) increased in poor metabolizers (PMs) (n = 48), 1.5-fold ( P < 0.001) increased in intermediate metabolizers (n = 238), and not significantly changed in ultrarapid metabolizers (n = 12). Compared with CYP2D6 normal metabolizers, treatment switch from vortioxetine to alternative antidepressants was 5.1-fold (95% confidence interval, 1.6-15.4, P = 0.003) more frequent among PMs. The prescribed doses did not differ significantly between the subgroups ( P = 0.26). A possible explanation for the increased frequency of treatment switch among PMs is that concentration-dependent adverse events were more frequent in this group because of increased drug exposure.

Conclusions: This naturalistic study provides novel data on the association between CYP2D6 genotype and treatment switch of vortioxetine, which likely reflects the significant effect of CYP2D6 genotype on vortioxetine exposure.