A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects

作者：Xin‐Mei Yang, Yang Yang, Bu‐Fan Yao, Panpan Ye, Yan Xu, Shao-Ping Peng, Yumei Yang, Shu Pan, LI Pei-jin, Shan Li, Honglin Hu, Qian Li, Linlin Song, Keguang Chen, Haiyan Zhou, Yehui Zhang, Furong Zhao, Bo‐Hao Tang, Wei Zhang, Xinfang Zhang, Shu-Meng Fu, Guo‐Xiang Hao, Yi Zheng, Jingshan Shen, Yechun Xu, Xiangrui Jiang, Leike Zhang, Renhong Tang, Wei Zhao · 发表于：European Journal of Pharmaceutical Sciences · 年份：2023 · DOI：10.1016/j.ejps.2023.106598 · 被引用次数：27 · 研究领域：SARS-CoV-2 and COVID-19 Research、SARS-CoV-2 detection and testing、Computational Drug Discovery Methods

Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further developm...