西莫特瑞韦/利托那韦的药物相互作用：一项开放标签、固定序列、两阶段的临床试验。

Drug-drug interactions of simnotrelvir/ritonavir: an open-label, fixed-sequence, two-period clinical trial.

作者信息

Ye Pan-Pan, Yao Bu-Fan, Yang Yang, Yang Xin-Mei, Li Qian, Song Lin-Lin, Chen Ke-Guang, Zhou Hai-Yan, Shi Jin-Yi, Zhang Ye-Hui, Zhao Fu-Rong, Guo Zi-Jia, Xu Shan-Sen, Chen Jia, Goh Aik Han, Zhu Shun-Wei, Zheng Yi, Zhao Wei

机构信息

Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China.

Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.

出版信息

Clin Microbiol Infect. 2025 Jan;31(1):101-107. doi: 10.1016/j.cmi.2024.09.007. Epub 2024 Sep 18.

DOI:10.1016/j.cmi.2024.09.007

PMID:39299559

Abstract

OBJECTIVES

Simnotrelvir is a small-molecule highly specific 3C-like protease inhibitor for anti-SARS-CoV-2 and was approved as a combination drug with ritonavir (simnotrelvir/ritonavir) in China. Simnotrelvir is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), and a weak inhibitor of CYP3A. Ritonavir is a substrate and inhibitor of CYP3A and an inhibitor of P-gp. Hence, the drug-drug interaction potential of simnotrelvir/ritonavir should be investigated.

METHODS

This drug-drug interaction study was an open-label, fixed-sequence, two-period phase I clinical trial in Chinese healthy adult subjects, divided into three cohorts, including simnotrelvir/ritonavir co-administrated with a strong CYP3A and P-gp inhibitor (itraconazole) and inducer (rifampicin), and with a specific CYP3A substrate (midazolam).

RESULTS

The results demonstrated that compared with administration of simnotrelvir/ritonavir alone, the co-administration with itraconazole increased the geometric least-square mean ratio (GMR) of the expose (area under the plasma concentration-time curve from time zero to the lowest detectable plasma concentration [AUC]) of simnotrelvir by 25% (GMR 125%, 90% CI 114-137%), whereas co-administration with rifampicin significantly decreased the AUC of simnotrelvir by 81.5% (GMR 18.5%, 90% CI 16.4-20.9%). Notably, simnotrelvir/ritonavir increased the AUC of midazolam by 16.69-fold (GMR 1769%, 90% CI 1551-2018%). The co-administration of simnotrelvir/ritonavir and rifampicin caused the increased amount and severity of treatment-emergent adverse events, especially hepatotoxicity.

DISCUSSION

The co-administration of simnotrelvir/ritonavir with CYP3A and P-gp inhibitors can be safely used, whereas the co-administration with CYP3A and P-gp strong inducer should be avoided to minimize the risk of under-exposure. Co-administration of midazolam with simnotrelvir/ritonavir increased systemic exposure of midazolam.

CLINICALTRIALS

gov Identifier: NCT05665647.

摘要

目的

西诺特韦是一种用于抗严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的小分子高特异性3C样蛋白酶抑制剂，在中国被批准作为与利托那韦的复方药物（西诺特韦/利托那韦）。西诺特韦是细胞色素P450 3A（CYP3A）和P-糖蛋白（P-gp）的底物，也是CYP3A的弱抑制剂。利托那韦是CYP3A的底物和抑制剂，也是P-gp的抑制剂。因此，应研究西诺特韦/利托那韦的药物相互作用潜力。

方法

这项药物相互作用研究是一项在中国健康成年受试者中进行的开放标签、固定序列、两期的I期临床试验，分为三个队列，包括西诺特韦/利托那韦与强效CYP3A和P-gp抑制剂（伊曲康唑）、诱导剂（利福平）联合给药，以及与特定CYP3A底物（咪达唑仑）联合给药。

结果

结果表明，与单独服用西诺特韦/利托那韦相比，与伊曲康唑联合给药使西诺特韦的暴露量（从零时间到最低可检测血浆浓度的血浆浓度-时间曲线下面积[AUC]）的几何最小二乘均值比（GMR）增加了25%（GMR 125%，90%置信区间114-137%），而与利福平联合给药显著降低了西诺特韦的AUC，降低了81.5%（GMR 18.5%，90%置信区间16.4-20.9%）。值得注意的是，西诺特韦/利托那韦使咪达唑仑的AUC增加了16.69倍（GMR 1769%，90%置信区间1551-2018%）。西诺特韦/利托那韦与利福平联合给药导致治疗中出现的不良事件数量增加且严重程度增加，尤其是肝毒性。