A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects
Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved..
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 development using this dosage as the clinically recommended dose regimen.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:191 |
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| Enthalten in: |
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences - 191(2023) vom: 01. Dez., Seite 106598 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Xin-Mei [VerfasserIn] |
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| Links: |
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| Themen: |
Antiviral Agents |
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| Anmerkungen: |
Date Completed 13.11.2023 Date Revised 13.11.2023 published: Print-Electronic ClinicalTrials.gov: NCT05339646 Citation Status MEDLINE |
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| doi: |
10.1016/j.ejps.2023.106598 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM362791562 |
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| 100 | 1 | |a Yang, Xin-Mei |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 13.11.2023 | ||
| 500 | |a Date Revised 13.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT05339646 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a 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 development using this dosage as the clinically recommended dose regimen | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a COVID-19 | |
| 650 | 4 | |a Healthy subjects | |
| 650 | 4 | |a Pharmacokinetics | |
| 650 | 4 | |a Safety | |
| 650 | 4 | |a Simnotrelvir | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Enzyme Inhibitors |2 NLM | |
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| 700 | 1 | |a Yang, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Bu-Fan |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Pan-Pan |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Shao-Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Yu-Mei |e verfasserin |4 aut | |
| 700 | 1 | |a Shu, Pan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Pei-Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Shan |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Hong-Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Lin-Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ke-Guang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Hai-Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ye-Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Fu-Rong |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Bo-Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xin-Fang |e verfasserin |4 aut | |
| 700 | 1 | |a Fu, Shu-Meng |e verfasserin |4 aut | |
| 700 | 1 | |a Hao, Guo-Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Jing-Shan |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Ye-Chun |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Xiang-Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Lei-Ke |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Ren-Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Wei |e verfasserin |4 aut | |
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