Brexpiprazole pharmacokinetics in CYP2D6 poor metabolizers: Using physiologically-based pharmacokinetic modeling to optimize time-to-effective concentrations (JCP-21-Apr-211-R2).

Abstract

Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia, or as adjunctive treatment for major depressive disorder (MDD). As CYP2D6 contributes significantly to brexpiprazole metabolism, there is a label-recommended 50% reduction in dose among patients with the CYP2D6 poor metabolizer phenotype. This study uses a whole-body physiologically-based pharmacokinetic (PBPK) model to compare the pharmacokinetics of brexpiprazole in patients known to be extensive (EM) and poor metabolizers (PMs). A PBPK model was constructed, verified, and validated against brexpiprazole clinical data, and simulations of 500 subjects were performed to establish the median time-to-effective concentrations in EMs and PMs. The PBPK simulations captured brexpiprazole PK well and demonstrated significant differences in the time to effective concentrations between EMs and PMs according to the label-recommended titration. Additionally, these simulations suggest that CYP2D6 PMs consistently achieve lower Ctrough concentrations than CYP2D6 EMs. Simulations using an alternative dosing strategy of BID dosing (as opposed to QD) in PMs during the first week of brexpiprazole dosing yielded more consistent plasma concentrations between EMs and PMs, without exceeding the AUC observed in the EMs. Taken together, the results of these PBPK simulations suggest that product labeling for brexpiprazole titration in CYP2D6 PMs likely overcompensates for the decreased clearance seen in this population. We propose an alternative dosing strategy that decreases the time to effective concentrations and recommend a re-evaluation of steady-state PK in this population to potentially allow for higher daily doses in CYP2D6 PMs. This article is protected by copyright. All rights reserved.