PMID- 37783378
OWN - NLM
STAT- MEDLINE
DCOM- 20231113
LR  - 20231113
IS  - 1879-0720 (Electronic)
IS  - 0928-0987 (Linking)
VI  - 191
DP  - 2023 Dec 1
TI  - A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for 
      treatment of COVID-19, in healthy adult subjects.
PG  - 106598
LID - S0928-0987(23)00228-2 [pii]
LID - 10.1016/j.ejps.2023.106598 [doi]
AB  - 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.
CI  - Copyright (c) 2023 The Author(s). Published by Elsevier B.V. All rights reserved.
FAU - Yang, Xin-Mei
AU  - Yang XM
AD  - 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, PR 
      China.
FAU - Yang, Yang
AU  - Yang Y
AD  - Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, PR China.
FAU - Yao, Bu-Fan
AU  - Yao BF
AD  - Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of 
      Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, 
      Shandong University, Jinan, PR China.
FAU - Ye, Pan-Pan
AU  - Ye PP
AD  - 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, PR 
      China.
FAU - Xu, Yan
AU  - Xu Y
AD  - Simcere of America, Cambridge, MA, USA.
FAU - Peng, Shao-Ping
AU  - Peng SP
AD  - Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, PR China.
FAU - Yang, Yu-Mei
AU  - Yang YM
AD  - Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, PR China.
FAU - Shu, Pan
AU  - Shu P
AD  - Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, PR China.
FAU - Li, Pei-Jin
AU  - Li PJ
AD  - Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, PR China.
FAU - Li, Shan
AU  - Li S
AD  - Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, PR China.
FAU - Hu, Hong-Lin
AU  - Hu HL
AD  - Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, PR China.
FAU - Li, Qian
AU  - Li Q
AD  - 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, PR 
      China.
FAU - Song, Lin-Lin
AU  - Song LL
AD  - 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, PR 
      China.
FAU - Chen, Ke-Guang
AU  - Chen KG
AD  - 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, PR 
      China.
FAU - Zhou, Hai-Yan
AU  - Zhou HY
AD  - 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, PR 
      China.
FAU - Zhang, Ye-Hui
AU  - Zhang YH
AD  - 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, PR 
      China.
FAU - Zhao, Fu-Rong
AU  - Zhao FR
AD  - 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, PR 
      China.
FAU - Tang, Bo-Hao
AU  - Tang BH
AD  - Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of 
      Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, 
      Shandong University, Jinan, PR China.
FAU - Zhang, Wei
AU  - Zhang W
AD  - Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of 
      Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, 
      Shandong University, Jinan, PR China.
FAU - Zhang, Xin-Fang
AU  - Zhang XF
AD  - Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of 
      Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, 
      Shandong University, Jinan, PR China.
FAU - Fu, Shu-Meng
AU  - Fu SM
AD  - Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of 
      Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, 
      Shandong University, Jinan, PR China.
FAU - Hao, Guo-Xiang
AU  - Hao GX
AD  - Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of 
      Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, 
      Shandong University, Jinan, PR China.
FAU - Zheng, Yi
AU  - Zheng Y
AD  - Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of 
      Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, 
      Shandong University, Jinan, PR China.
FAU - Shen, Jing-Shan
AU  - Shen JS
AD  - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR 
      China.
FAU - Xu, Ye-Chun
AU  - Xu YC
AD  - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR 
      China.
FAU - Jiang, Xiang-Rui
AU  - Jiang XR
AD  - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR 
      China.
FAU - Zhang, Lei-Ke
AU  - Zhang LK
AD  - State Key Laboratory of Virology, Wuhan Institute of Virology, Center for 
      Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, PR China.
FAU - Tang, Ren-Hong
AU  - Tang RH
AD  - Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, PR China.
FAU - Zhao, Wei
AU  - Zhao W
AD  - 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, PR 
      China; Department of Clinical Pharmacy, Key Laboratory of Chemical Biology 
      (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of 
      Medicine, Shandong University, Jinan, PR China. Electronic address: 
      zhao4wei2@hotmail.com.
LA  - eng
SI  - ClinicalTrials.gov/NCT05339646
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20230930
PL  - Netherlands
TA  - Eur J Pharm Sci
JT  - European journal of pharmaceutical sciences : official journal of the European 
      Federation for Pharmaceutical Sciences
JID - 9317982
RN  - 0 (Antiviral Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Protease Inhibitors)
RN  - O3J8G9O825 (Ritonavir)
SB  - IM
MH  - Adult
MH  - Humans
MH  - Antiviral Agents/adverse effects
MH  - *COVID-19
MH  - Enzyme Inhibitors
MH  - Healthy Volunteers
MH  - *Protease Inhibitors/adverse effects
MH  - Ritonavir/therapeutic use
MH  - SARS-CoV-2
OTO - NOTNLM
OT  - COVID-19
OT  - Healthy subjects
OT  - Pharmacokinetics
OT  - Safety
OT  - Simnotrelvir
COIS- 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.
EDAT- 2023/10/03 00:42
MHDA- 2023/11/06 06:42
CRDT- 2023/10/02 19:24
PHST- 2023/06/10 00:00 [received]
PHST- 2023/09/22 00:00 [revised]
PHST- 2023/09/25 00:00 [accepted]
PHST- 2023/11/06 06:42 [medline]
PHST- 2023/10/03 00:42 [pubmed]
PHST- 2023/10/02 19:24 [entrez]
AID - S0928-0987(23)00228-2 [pii]
AID - 10.1016/j.ejps.2023.106598 [doi]
PST - ppublish
SO  - Eur J Pharm Sci. 2023 Dec 1;191:106598. doi: 10.1016/j.ejps.2023.106598. Epub 
      2023 Sep 30.