Clinical Drug Investigation ( IF 2.9 ) Pub Date : 2023-05-12 , DOI: 10.1007/s40261-023-01265-8 Ryosuke Shimizu 1 , Takuhiro Sonoyama 2 , Takahiro Fukuhara 3 , Aya Kuwata 3 , Takanobu Matsuzaki 4 , Yumiko Matsuo 1, 5 , Ryuji Kubota 1
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Background
Management of drug–drug interactions (DDIs) for ensitrelvir, a novel 3-chymotrypsin-like protease inhibitor of SARS-CoV-2 infection is crucial. A previous clinical DDI study of ensitrelvir with midazolam, a clinical index cytochrome P450 (CYP) 3A substrate, demonstrated that ensitrelvir given for 5 days orally with a loading/maintenance dose of 750/250 mg acted as a strong CYP3A inhibitor.
Objectives
The objectives of this study were to investigate the effect of ensitrelvir on the pharmacokinetics of CYP3A substrates, dexamethasone, prednisolone and midazolam, and to assess the pharmacokinetics, safety, and tolerability of ensitrelvir following multiple-dose administration of ensitrelvir.
Methods
This was a Phase 1, multicenter, single-arm, open-label study in healthy Japanese adult participants. The effects of multiple doses of ensitrelvir in the fasted state on the pharmacokinetics of dexamethasone, prednisolone, and midazolam were investigated. Ensitrelvir was administered from Day 1 through Day 5, with a loading/maintenance dose of 750/250 mg for the dexamethasone and prednisolone cohorts whereas 375/125 mg for the midazolam cohort. Either dexamethasone, prednisolone, or midazolam was administered alone (Day − 2) or in combination with ensitrelvir (Day 5) in each of the cohorts. Additionally, dexamethasone or prednisolone was administered on Days 9 and 14. The pharmacokinetic parameters of ensitrelvir, dexamethasone, prednisolone, and midazolam were calculated based on their plasma concentration data with non-compartmental analysis. In safety assessments, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded.
Results
The area under the concentration-time curve (AUC) ratio of dexamethasone on Day 5 was 3.47-fold compared with the corresponding values for dexamethasone alone on Day − 2 and the effect diminished over time after the last dose of ensitrelvir. No clinically meaningful effect was observed for prednisolone. The AUC ratio of midazolam was 6.77-fold with ensitrelvir 375/125 mg suggesting ensitrelvir at 375/125 mg strongly inhibits CYP3A similar to that at 750/250 mg. No new safety signals with ensitrelvir were reported during the study.
Conclusion
The inhibitory effect for CYP3A was confirmed after the last dose of ensitrelvir, and the effect diminished over time. In addition, ensitrelvir at 375/125 mg showed CYP3A inhibitory potential similar to that at 750/250 mg. These findings can be used as a clinical recommendation for prescribing ensitrelvir with regard to concomitant medications.
Clinical Trial Registration
Japan Registry of Clinical Trials identifier: jRCT2031210202.
中文翻译：
恩西瑞韦富马酸与细胞色素 P450 3A 底物在健康日本成人中的药物相互作用潜力评估
背景
ensitrelvir 是一种新型 3-胰凝乳蛋白酶样蛋白酶抑制剂，用于治疗 SARS-CoV-2 感染，对药物相互作用 (DDI) 的管理至关重要。先前一项恩西瑞韦与咪达唑仑（一种临床指标细胞色素 P450 (CYP) 3A 底物）联合使用的临床 DDI 研究表明，恩西瑞韦口服 5 天，负荷/维持剂量为 750/250 mg，可作为强效 CYP3A 抑制剂。
目标
本研究的目的是研究恩西瑞韦对 CYP3A 底物、地塞米松、泼尼松龙和咪达唑仑药代动力学的影响，并评估多剂量给予恩西瑞韦后的药代动力学、安全性和耐受性。
方法
这是一项针对健康日本成人参与者的第一阶段、多中心、单臂、开放标签研究。研究了空腹状态下多次剂量恩西瑞韦对地塞米松、泼尼松龙和咪达唑仑药代动力学的影响。恩西瑞韦从第 1 天到第 5 天给药，地塞米松和泼尼松龙组的负荷/维持剂量为 750/250 mg，而咪达唑仑组的负荷/维持剂量为 375/125 mg。每个队列中单独使用地塞米松、泼尼松龙或咪达唑仑（第 2 天）或与恩西瑞韦联合使用（第 5 天）。此外，在第9天和第14天给予地塞米松或泼尼松龙。恩西瑞韦、地塞米松、泼尼松龙和咪达唑仑的药代动力学参数是根据其血浆浓度数据通过非房室分析计算的。在安全性评估中，评估并记录治疗中出现的不良事件的性质、频率和严重程度。
结果
与第 2 天单独使用地塞米松的相应值相比，第 5 天地塞米松的浓度-时间曲线下面积 (AUC) 比率为 3.47 倍，并且在最后一次服用恩西瑞韦后，效果随着时间的推移而减弱。泼尼松龙没有观察到有临床意义的作用。咪达唑仑的 AUC 比率为 ensitrelvir 375/125 mg 的 6.77 倍，表明 ensitrelvir 375/125 mg 强烈抑制 CYP3A，与 750/250 mg 相似。研究期间没有报告恩西瑞韦的新安全信号。
结论
在最后一次服用恩西瑞韦后，证实了对 CYP3A 的抑制作用，并且该作用随着时间的推移而减弱。此外，375/125 mg 的 enitrelvir 显示出与 750/250 mg 相似的 CYP3A 抑制潜力。这些发现可作为开具恩西瑞韦联合用药的临床建议。
临床试验注册
日本临床试验登记处标识符：jRCT2031210202。
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