在健康个体中评估阿布昔替尼对细胞色素 P450 1A2、2B6 和 2C19 酶和激素口服避孕药探针底物药代动力学的影响。
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.
机构信息
Pfizer Inc, Groton, CT, USA.
Pfizer Inc, Cambridge, MA, USA.
出版信息
Eur J Drug Metab Pharmacokinet. 2024 May;49(3):367-381. doi: 10.1007/s13318-024-00893-5. Epub 2024 Mar 30.
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 (AUC) and the maximum concentration (C) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUC of caffeine by 40% with lack of effect on C.
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.
背景和目的
阿布昔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，阿布昔替尼是细胞色素 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。为评估阿布昔替尼对伴随药物的潜在影响，对阿布昔替尼与这些 CYP 酶的敏感探针底物进行了药物相互作用（DDI）研究。还评估了阿布昔替尼对激素口服避孕药（炔雌醇和左炔诺孕酮）的影响，这些药物是 CYP3A 的底物，也是女性患者的重要伴随药物。
方法
进行了三项 1 期 DDI 研究，以评估阿布昔替尼 200mg 每日一次（QD）对以下探针底物的影响：（1）CYP1A2（咖啡因）、2B6（依非韦伦）和 2C19（奥美拉唑）的鸡尾酒研究；（2）CYP3A（咪达唑仑）；（3）CYP3A（避孕药）。
结果
阿布昔替尼 200mg QD 多次给药后，咪达唑仑、依非韦伦和避孕药的药代动力学无影响。阿布昔替尼使奥美拉唑的 AUC0-∞和 Cmax 分别增加约 189%和 134%。阿布昔替尼使咖啡因的 AUC 增加 40%，但 C 无影响。
结论
根据研究结果，阿布昔替尼是 CYP2C19 的中度抑制剂。当与主要通过 CYP2C19 酶代谢的治疗指数较窄的药物同时使用时，应谨慎使用阿布昔替尼。阿布昔替尼是 CYP1A2 的轻度抑制剂；然而，其影响无临床意义，不建议对 CYP1A2 底物进行一般剂量调整。阿布昔替尼不抑制 CYP3A 或诱导 CYP1A2/2B6/2C19/3A，不影响避孕药的药代动力学。
临床试验注册
ClinicalTrials.gov 注册号：NCT03647670、NCT05067439、NCT03662516。
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