Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Xiaoxing Wang, Martin E Dowty, Sakambari Tripathy, Vu H Le, Yeamin Huh, Madelyn Curto, Jennifer A Winton, Melissa T O'Gorman, Gary Chan, Bimal K Malhotra
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引用次数: 0

Abstract

Background and objective: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated.

Methods: Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives).

Results: After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax.

Conclusions: Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives.

Clinical trials registration: ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.

评估阿罗昔替尼对健康人体内细胞色素 P450 1A2、2B6 和 2C19 酶的探针底物以及激素类口服避孕药的药代动力学的影响。
背景和目的阿罗西替尼是一种口服小分子Janus激酶(JAK)-1抑制剂,已被批准用于治疗中重度特应性皮炎。体外研究表明,阿罗西替尼是细胞色素P450(CYP)2C19/3A的弱时间依赖性抑制剂,也是CYP1A2/2B6/2C19/3A的弱诱导剂。为了评估阿罗西替尼对并用药物的潜在影响,研究人员对阿罗西替尼与这些CYP酶的敏感探针底物进行了药物相互作用(DDI)研究。此外,还评估了阿罗西替尼对激素类口服避孕药(炔雌醇和左炔诺孕酮)的影响:进行了三项 1 期 DDI 研究,以评估阿罗西替尼 200 毫克每日一次(QD)对以下探针底物的影响:(方法:进行了三项1期DDI研究,评估阿罗西替尼200毫克,每日一次(QD)对以下探针底物的影响:(1) 鸡尾酒研究中的1A2(咖啡因)、2B6(依非韦伦)和2C19(奥美拉唑);(2) 3A(咪达唑仑);(3) 3A(口服避孕药):结果:多次服用阿罗西替尼 200 毫克 QD 后,对咪达唑仑、依非韦伦和避孕药的药代动力学没有影响。阿罗昔替尼使奥美拉唑从0到无穷大的浓度时间曲线下面积(AUCinf)和最大浓度(Cmax)分别增加了约189%和134%。阿洛西替尼使咖啡因的AUCinf增加了40%,但对Cmax没有影响:根据研究结果,阿罗西替尼是CYP2C19的中度抑制剂。当阿罗西替尼与主要由CYP2C19酶代谢的窄治疗指数药物同时使用时应谨慎。阿罗西替尼是 CYP1A2 的轻度抑制剂,但其影响与临床无关,因此不建议对 CYP1A2 底物进行一般剂量调整。阿罗昔替尼不会抑制CYP3A或诱导CYP1A2/2B6/2C19/3A,也不会影响避孕药的药代动力学:临床试验注册:ClinicalTrials.gov 注册 IDs:NCT03647670、NCT05067439、NCT03662516。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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