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

Yang et al., European Journal of Pharmaceutical Sciences, doi:10.1016/j.ejps.2023.106598, NCT05339646
Dec 2023  
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RCT 72 healthy subjects evaluating safety, tolerability, and pharmacokinetics of simnotrelvir (SSD8432, SIM0417), a 3CL protease inhibitor, alone or co-administered with ritonavir at various single and multiple ascending oral doses and under different fed conditions. The combination was well-tolerated with mostly mild adverse events. Simnotrelvir exposure increased approximately dose-proportionally from 250-750 mg twice daily when boosted by ritonavir, with steady state reached by day 3. Food intake significantly increased simnotrelvir exposure. Based on achieving trough concentrations above the EC90 target for SARS-CoV-2 inhibition throughout the dosing interval, the results support further development of simnotrelvir/ritonavir 750 mg/100 mg twice daily without food as the recommended regimen for COVID-19 treatment.
Yang et al., 31 Dec 2023, Double Blind Randomized Controlled Trial, placebo-controlled, China, peer-reviewed, 29 authors, trial NCT05339646 (history). Contact:
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A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects
Xin-Mei Yang, Yang Yang, Bu-Fan Yao, Pan-Pan Ye, Yan Xu, Shao-Ping Peng, Yu-Mei Yang, Pan Shu, Pei-Jin Li, Shan Li, Hong-Lin Hu, Qian Li, Lin-Lin Song, Ke-Guang Chen, Hai-Yan Zhou, Ye-Hui Zhang, Fu-Rong Zhao, Bo-Hao Tang, Wei Zhang, Xin-Fang Zhang, Shu-Meng Fu, Guo-Xiang Hao, Yi Zheng, Jing-Shan Shen, Ye-Chun Xu, Xiang-Rui Jiang, Lei-Ke Zhang, Ren-Hong Tang, Wei Zhao
European Journal of Pharmaceutical Sciences, doi:10.1016/j.ejps.2023.106598
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 ( 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 development using this dosage as the clinically recommended dose regimen.
Declaration of Competing Interest Yang Yang, Shao-Ping Peng, Yu-Mei Yang, Pan Shu, Pei-Jin Li, Shan Li, Hong-Lin Hu and Ren-Hong Tang are employees of Jiangsu Simcere Pharmaceutical Co., Ltd. Yan Xu is employee of Simcere of America. Other authors declare that they have no conflict of interest. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ejps.2023.106598.
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