tetano
Editor, Senior Moderator
Eur J Pharm Sci
. 2023 Sep 30;106598.
doi: 10.1016/j.ejps.2023.106598. Online ahead of print. 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[SUP] 1 [/SUP], Yang Yang[SUP] 2 [/SUP], Bu-Fan Yao[SUP] 3 [/SUP], Pan-Pan Ye[SUP] 1 [/SUP], Yan Xu[SUP] 4 [/SUP], Shao-Ping Peng[SUP] 2 [/SUP], Yu-Mei Yang[SUP] 2 [/SUP], Pan Shu[SUP] 2 [/SUP], Pei-Jin Li[SUP] 2 [/SUP], Shan Li[SUP] 2 [/SUP], Hong-Lin Hu[SUP] 2 [/SUP], Qian Li[SUP] 1 [/SUP], Lin-Lin Song[SUP] 1 [/SUP], Ke-Guang Chen[SUP] 1 [/SUP], Hai-Yan Zhou[SUP] 1 [/SUP], Ye-Hui Zhang[SUP] 1 [/SUP], Fu-Rong Zhao[SUP] 1 [/SUP], Bo-Hao Tang[SUP] 3 [/SUP], Wei Zhang[SUP] 3 [/SUP], Xin-Fang Zhang[SUP] 3 [/SUP], Shu-Meng Fu[SUP] 3 [/SUP], Guo-Xiang Hao[SUP] 3 [/SUP], Yi Zheng[SUP] 3 [/SUP], Jing-Shan Shen[SUP] 5 [/SUP], Ye-Chun Xu[SUP] 5 [/SUP], Xiang-Rui Jiang[SUP] 5 [/SUP], Lei-Ke Zhang[SUP] 6 [/SUP], Ren-Hong Tang[SUP] 2 [/SUP], Wei Zhao[SUP] 7 [/SUP]
Affiliations
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 250-750 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 750mg/100mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.
Keywords: COVID-19; healthy subjects; pharmacokinetics; safety; simnotrelvir.
. 2023 Sep 30;106598.
doi: 10.1016/j.ejps.2023.106598. Online ahead of print. 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[SUP] 1 [/SUP], Yang Yang[SUP] 2 [/SUP], Bu-Fan Yao[SUP] 3 [/SUP], Pan-Pan Ye[SUP] 1 [/SUP], Yan Xu[SUP] 4 [/SUP], Shao-Ping Peng[SUP] 2 [/SUP], Yu-Mei Yang[SUP] 2 [/SUP], Pan Shu[SUP] 2 [/SUP], Pei-Jin Li[SUP] 2 [/SUP], Shan Li[SUP] 2 [/SUP], Hong-Lin Hu[SUP] 2 [/SUP], Qian Li[SUP] 1 [/SUP], Lin-Lin Song[SUP] 1 [/SUP], Ke-Guang Chen[SUP] 1 [/SUP], Hai-Yan Zhou[SUP] 1 [/SUP], Ye-Hui Zhang[SUP] 1 [/SUP], Fu-Rong Zhao[SUP] 1 [/SUP], Bo-Hao Tang[SUP] 3 [/SUP], Wei Zhang[SUP] 3 [/SUP], Xin-Fang Zhang[SUP] 3 [/SUP], Shu-Meng Fu[SUP] 3 [/SUP], Guo-Xiang Hao[SUP] 3 [/SUP], Yi Zheng[SUP] 3 [/SUP], Jing-Shan Shen[SUP] 5 [/SUP], Ye-Chun Xu[SUP] 5 [/SUP], Xiang-Rui Jiang[SUP] 5 [/SUP], Lei-Ke Zhang[SUP] 6 [/SUP], Ren-Hong Tang[SUP] 2 [/SUP], Wei Zhao[SUP] 7 [/SUP]
Affiliations
- PMID: 37783378
- 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 (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 250-750 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 750mg/100mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.
Keywords: COVID-19; healthy subjects; pharmacokinetics; safety; simnotrelvir.