Impact of age and CYP2D6 genetics on exposure of aripiprazole and dehydroaripiprazole in patients using long-acting injectable versus oral formulation: relevance of poor and intermediate metabolizer status.

Abstract

Tailoring medication dosing for the individual patient is complex, and many factors can influence drug exposure. We investigated the effect of age and CYP2D6 genotype on aripiprazole and dehydroaripiprazole exposure in patients using long-acting injectable (LAI) or oral aripiprazole. Matched data on serum concentration of aripiprazole and CYP2D6 genotype of patients using oral or LAI aripiprazole were included retrospectively from a therapeutic drug monitoring service. The patients were divided into the following CYP2D6 genotype-defined categories: poor metabolizers (PMs), intermediate metabolizers (IMs), normal metabolizers (NMs), and ultrarapid metabolizers (UMs). Linear mixed model analyses were used to evaluate the impact of CYP2D6 genotype on dose-adjusted serum concentrations of the active moiety of aripiprazole+dehydroaripiprazole in relation to age and formulation. We identified 635 patients (mean age = 40.1 years, 9.4% ≥ 65 years, 53.7% females) using LAI (n = 166) or oral formulation (n = 469). The genotype-predicted CYP2D6 phenotype subgroups were 2.4% UMs, 82.0% NMs, 8.0% IMs, and 7.2% PMs. Age did not significantly affect exposure of the active moiety of aripiprazole+dehydroaripiprazole in the LAI (p = 0.071) or oral (p = 0.14) subgroups. Compared with CYP2D6 NMs, PMs and IMs had significantly increased exposure of the active moiety of aripiprazole+dehydroaripiprazole in the LAI (1.7-fold higher, p < 0.001, and 1.5-fold higher, p < 0.001) and oral (1.7-fold higher, p < 0.001, and 1.6-fold higher, p < 0.001) subgroups. In conclusion, doses should be adjusted according to CYP2D6 genotype when initiating treatment with aripiprazole LAI or tablets, while advanced age do not affect the exposure of the active moiety of aripiprazole treatment regardless of formulation.