Bruno Christopher D, Elmokadem Ahmed, Housand Conrad, Jordie Eric Burroughs, Chow Christina R, Laughren Thomas P, Greenblatt David J
Emerald Lake Safety, Newport Beach, California, USA.
Tufts University School of Medicine, Boston, Massachusetts, USA.
J Clin Pharmacol. 2022 Jan;62(1):55-65. doi: 10.1002/jcph.1947. Epub 2021 Aug 26.
Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia or as adjunctive treatment for major depressive disorder. As obesity (body mass index ≥35 kg/m ) has the potential to affect drug pharmacokinetics and is a common comorbidity of both schizophrenia and major depressive disorder, it is important to understand changes in brexpiprazole disposition in this population. This study uses a whole-body physiologically based pharmacokinetic model to compare the pharmacokinetics of brexpiprazole in obese and normal-weight (body mass index 18-25 kg/m ) individuals known to be cytochrome P450 2D6 extensive metabolizers (EMs) and poor metabolizers (PMs). The physiologically based pharmacokinetic 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 1 week of twice-daily dosing in obese EMs or 2 weeks of twice-daily dosing in obese poor metabolizers, followed by a return to once-daily dosing, yielded more consistent plasma concentrations between normal-weight and obese patients without exceeding the area under the plasma concentration-time curve 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.
布雷哌唑是一种口服抗精神病药物，适用于精神分裂症患者或作为重度抑郁症的辅助治疗药物。由于肥胖（体重指数≥35 kg/m²）有可能影响药物的药代动力学，且是精神分裂症和重度抑郁症的常见合并症，因此了解该人群中布雷哌唑处置情况的变化很重要。本研究使用基于生理的全身药代动力学模型，比较已知为细胞色素P450 2D6广泛代谢者（EMs）和慢代谢者（PMs）的肥胖个体与正常体重个体（体重指数18 - 25 kg/m²）中布雷哌唑的药代动力学。基于生理的药代动力学模拟表明，根据标签推荐的滴定法，代谢者组内肥胖个体与正常体重个体达到有效浓度的时间存在显著差异。在肥胖EMs中采用每日两次给药1周或肥胖PMs中采用每日两次给药2周，然后恢复为每日一次给药的替代给药策略进行模拟，结果显示正常体重和肥胖患者之间的血浆浓度更一致，且未超过正常体重EMs中观察到的血浆浓度-时间曲线下面积。这些替代给药策略可缩短肥胖患者达到有效浓度的时间，并可能改善对布雷哌唑的临床反应。
