Journal of clinical pharmacology | 2021
Impact of Obesity on Brexpiprazole Pharmacokinetics: Proposal for Improved Initiation of Treatment (JCP-21-Apr-212-R1).
Abstract
Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia, or as adjunctive treatment for major depressive disorder (MDD). As obesity (BMI ≥35 kg/m2 ) has the potential to affect drug pharmacokinetics and is a common comorbidity of both schizophrenia and MDD, it is important to understand changes in brexpiprazole disposition in this population. This study utilizes a whole-body physiologically-based pharmacokinetic (PBPK) model to compare the pharmacokinetics of brexpiprazole in obese and normal-weight (BMI 18-25 kg/m2 ) individuals known to be CYP2D6 extensive (EM) and poor metabolizers (PMs). The PBPK simulations demonstrated significant differences in the time to effective concentrations between obese and normal-weight individuals within metabolizer groups according to the label-recommended titration. Simulations using an alternative dosing strategy of one week of BID dosing in obese EMs or two weeks of BID dosing in obese PMs, followed by a return to once daily dosing, yielded more consistent plasma concentrations between normal-weight and obese patients without exceeding the AUC observed in the normal-weight EMs. These alternative dosing strategies reduce the time to effective concentrations in obese patients and may improve clinical response to brexpiprazole. This article is protected by copyright. All rights reserved.