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 (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.
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.
References
Association, World medical association declaration of helsinki ethical principles for medical research involving human subjects, JAMA,
doi:10.1001/jama.2013.281053Cde, Technical guidelines for clinical pharmacokinetic research of chemical drugs
Cde, Technical guidelines for population pharmacokinetic research
Eng, Dantonio, Kadar, Obach, Di et al., Disposition of nirmatrelvir, an orally bioavailable inhibitor of SARS-CoV-2 3C-like protease, across animals and humans, Drug Metab. Dispos,
doi:10.1124/dmd.121.000801Ich, Integrated addendum to ICH E6(R1): guideline for good clinical practice E6 (R2)
Kushwah, Arora, Tamás Katona, Modhave, Fröhlich et al., On absorption modeling and food effect prediction of rivaroxaban, a BCS II drug orally administered as an immediate-release tablet, Pharmaceutics,
doi:10.3390/pharmaceutics13020283Miyake, Oka, Mukai, Food effect on meal administration time of pharmacokinetic profile of cilostazol, a BCS class II drug, Xenobiotica,
doi:10.1080/00498254.2019.1602746Naqvi, Fatima, Mohammad, Fatima, Singh et al., Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: structural genomics approach, Biochimica et biophysica acta. Mol. Basis Disease,
doi:10.1016/j.bbadis.2020.165878Ng, Correia, Seagal, Degoey, Schrimpf et al., Antiviral drug discovery for the treatment of COVID-19 infections, Viruses,
doi:10.3390/v14050961Owen, Allerton, Anderson, Aschenbrenner, Avery et al., An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19, Science,
doi:10.1126/science.abl4784Sevrioukova, Poulos, Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir, Proc. Natl. Acad. Sci. U.S.A,
doi:10.1073/pnas.1010693107Singh, Toussi, Hackman, Chan, Rao et al., Innovative randomized phase I study and dosing regimen selection to accelerate and inform pivotal COVID-19 trial of nirmatrelvir, Clin. Pharmacol. Ther,
doi:10.1002/cpt.2603{ 'indexed': {'date-parts': [[2024, 1, 25]], 'date-time': '2024-01-25T13:01:41Z', 'timestamp': 1706187701994},
'reference-count': 18,
'publisher': 'Elsevier BV',
'license': [ { 'start': { 'date-parts': [[2023, 12, 1]],
'date-time': '2023-12-01T00:00:00Z',
'timestamp': 1701388800000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'https://www.elsevier.com/tdm/userlicense/1.0/'},
{ 'start': { 'date-parts': [[2023, 9, 25]],
'date-time': '2023-09-25T00:00:00Z',
'timestamp': 1695600000000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'http://creativecommons.org/licenses/by/4.0/'}],
'content-domain': {'domain': ['elsevier.com', 'sciencedirect.com'], 'crossmark-restriction': True},
'published-print': {'date-parts': [[2023, 12]]},
'DOI': '10.1016/j.ejps.2023.106598',
'type': 'journal-article',
'created': {'date-parts': [[2023, 9, 30]], 'date-time': '2023-09-30T07:41:45Z', 'timestamp': 1696059705000},
'page': '106598',
'update-policy': 'http://dx.doi.org/10.1016/elsevier_cm_policy',
'source': 'Crossref',
'is-referenced-by-count': 3,
'title': 'A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of '
'COVID-19, in healthy adult subjects',
'prefix': '10.1016',
'volume': '191',
'author': [ {'given': 'Xin-Mei', 'family': 'Yang', 'sequence': 'first', 'affiliation': []},
{'given': 'Yang', 'family': 'Yang', 'sequence': 'additional', 'affiliation': []},
{'given': 'Bu-Fan', 'family': 'Yao', 'sequence': 'additional', 'affiliation': []},
{'given': 'Pan-Pan', 'family': 'Ye', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yan', 'family': 'Xu', 'sequence': 'additional', 'affiliation': []},
{'given': 'Shao-Ping', 'family': 'Peng', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yu-Mei', 'family': 'Yang', 'sequence': 'additional', 'affiliation': []},
{'given': 'Pan', 'family': 'Shu', 'sequence': 'additional', 'affiliation': []},
{'given': 'Pei-Jin', 'family': 'Li', 'sequence': 'additional', 'affiliation': []},
{'given': 'Shan', 'family': 'Li', 'sequence': 'additional', 'affiliation': []},
{'given': 'Hong-Lin', 'family': 'Hu', 'sequence': 'additional', 'affiliation': []},
{'given': 'Qian', 'family': 'Li', 'sequence': 'additional', 'affiliation': []},
{'given': 'Lin-Lin', 'family': 'Song', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ke-Guang', 'family': 'Chen', 'sequence': 'additional', 'affiliation': []},
{'given': 'Hai-Yan', 'family': 'Zhou', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ye-Hui', 'family': 'Zhang', 'sequence': 'additional', 'affiliation': []},
{'given': 'Fu-Rong', 'family': 'Zhao', 'sequence': 'additional', 'affiliation': []},
{'given': 'Bo-Hao', 'family': 'Tang', 'sequence': 'additional', 'affiliation': []},
{'given': 'Wei', 'family': 'Zhang', 'sequence': 'additional', 'affiliation': []},
{'given': 'Xin-Fang', 'family': 'Zhang', 'sequence': 'additional', 'affiliation': []},
{'given': 'Shu-Meng', 'family': 'Fu', 'sequence': 'additional', 'affiliation': []},
{'given': 'Guo-Xiang', 'family': 'Hao', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yi', 'family': 'Zheng', 'sequence': 'additional', 'affiliation': []},
{'given': 'Jing-Shan', 'family': 'Shen', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ye-Chun', 'family': 'Xu', 'sequence': 'additional', 'affiliation': []},
{'given': 'Xiang-Rui', 'family': 'Jiang', 'sequence': 'additional', 'affiliation': []},
{'given': 'Lei-Ke', 'family': 'Zhang', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ren-Hong', 'family': 'Tang', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-1830-338X',
'authenticated-orcid': False,
'given': 'Wei',
'family': 'Zhao',
'sequence': 'additional',
'affiliation': []}],
'member': '78',
'reference': [ { 'key': '10.1016/j.ejps.2023.106598_bib0001',
'series-title': 'Emergency Use Authorization (EUA) For Paxlovid (Niematrelvir Tablets '
'Co-Packaged With Ritonavir Tablets)',
'year': '2021'},
{ 'issue': '20',
'key': '10.1016/j.ejps.2023.106598_bib0002',
'doi-asserted-by': 'crossref',
'first-page': '2191',
'DOI': '10.1001/jama.2013.281053',
'article-title': 'World medical association declaration of helsinki ethical principles '
'for medical research involving human subjects',
'volume': '310',
'year': '2013',
'journal-title': 'JAMA'},
{ 'key': '10.1016/j.ejps.2023.106598_bib0003',
'unstructured': 'CDE, 2020. Technical guidelines for population pharmacokinetic research. '
'https://www.cde.org.cn/main/news/viewInfoCommon/b3e8205a4749caa0264414514cdf45ac '
'(accessed 20 Jul 2023).'},
{ 'key': '10.1016/j.ejps.2023.106598_bib0004',
'unstructured': 'CDE, 2005. Technical guidelines for clinical pharmacokinetic research of '
'chemical drugs. '
'https://www.cde.org.cn/zdyz/domesticinfopage?zdyzIdCODE=4247ffceca57f2b47aa0f67a3fdc7c43 '
'(accessed 20 Jul 2023).'},
{ 'issue': '5',
'key': '10.1016/j.ejps.2023.106598_bib0006',
'doi-asserted-by': 'crossref',
'first-page': '576',
'DOI': '10.1124/dmd.121.000801',
'article-title': 'Disposition of nirmatrelvir, an orally bioavailable inhibitor of '
'SARS-CoV-2 3C-like protease, across animals and humans',
'volume': '50',
'author': 'Eng',
'year': '2022',
'journal-title': 'Drug Metab. Dispos.'},
{ 'key': '10.1016/j.ejps.2023.106598_bib0007',
'unstructured': 'ICH, 2016. Integrated addendum to ICH E6(R1): guideline for good '
'clinical practice E6(R2). '
'https://www.gmp-compliance.org/files/guidemgr/E6_R2__Step_4.pdf '
'(accessed 9 Jun 2023).'},
{ 'issue': '2',
'key': '10.1016/j.ejps.2023.106598_bib0008',
'doi-asserted-by': 'crossref',
'first-page': '283',
'DOI': '10.3390/pharmaceutics13020283',
'article-title': 'On absorption modeling and food effect prediction of rivaroxaban, a BCS '
'II drug orally administered as an immediate-release tablet',
'volume': '13',
'author': 'Kushwah',
'year': '2021',
'journal-title': 'Pharmaceutics'},
{ 'issue': '5',
'key': '10.1016/j.ejps.2023.106598_bib0009',
'doi-asserted-by': 'crossref',
'first-page': '585',
'DOI': '10.1007/s40265-022-01692-5',
'article-title': 'Nirmatrelvir plus ritonavir: first approval',
'volume': '82',
'author': 'Lamb',
'year': '2022',
'journal-title': 'Drugs'},
{ 'key': '10.1016/j.ejps.2023.106598_bib0010',
'doi-asserted-by': 'crossref',
'first-page': '241',
'DOI': '10.1007/978-981-13-7647-4_5',
'article-title': 'Transporter-mediated drug-drug interactions and their significance',
'volume': '1141',
'author': 'Liu',
'year': '2019',
'journal-title': 'Adv. Exp. Med. Biol.'},
{ 'key': '10.1016/j.ejps.2023.106598_bib0011',
'doi-asserted-by': 'crossref',
'DOI': '10.1016/j.antiviral.2022.105419',
'article-title': 'Repurposing of HIV/HCV protease inhibitors against SARS-CoV-2 3CLpro',
'volume': '207',
'author': 'Ma',
'year': '2022',
'journal-title': 'Antiviral Res.'},
{ 'issue': '2',
'key': '10.1016/j.ejps.2023.106598_bib0012',
'doi-asserted-by': 'crossref',
'first-page': '145',
'DOI': '10.1080/00498254.2019.1602746',
'article-title': 'Food effect on meal administration time of pharmacokinetic profile of '
'cilostazol, a BCS class II drug',
'volume': '50',
'author': 'Miyake',
'year': '2020',
'journal-title': 'Xenobiotica'},
{ 'issue': '5',
'key': '10.1016/j.ejps.2023.106598_bib0013',
'doi-asserted-by': 'crossref',
'first-page': '961',
'DOI': '10.3390/v14050961',
'article-title': 'Antiviral drug discovery for the treatment of COVID-19 infections',
'volume': '14',
'author': 'Ng',
'year': '2022',
'journal-title': 'Viruses'},
{ 'issue': '14',
'key': '10.1016/j.ejps.2023.106598_bib0014',
'doi-asserted-by': 'crossref',
'first-page': '7692',
'DOI': '10.3390/ijms22147692',
'article-title': 'The impact of diet and exercise on drug responses',
'volume': '22',
'author': 'Niederberger',
'year': '2021',
'journal-title': 'Int. J. Mol. Sci'},
{ 'issue': '10',
'key': '10.1016/j.ejps.2023.106598_bib0015',
'doi-asserted-by': 'crossref',
'DOI': '10.1016/j.bbadis.2020.165878',
'article-title': 'Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and '
'therapies: structural genomics approach. Biochimica et biophysica acta',
'volume': '1866',
'author': 'Naqvi',
'year': '2020',
'journal-title': 'Mol. Basis Disease'},
{ 'issue': '6575',
'key': '10.1016/j.ejps.2023.106598_bib0016',
'doi-asserted-by': 'crossref',
'first-page': '1586',
'DOI': '10.1126/science.abl4784',
'article-title': 'An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment '
'of COVID-19',
'volume': '374',
'author': 'Owen',
'year': '2021',
'journal-title': 'Science (New York, N.Y.).'},
{ 'issue': '1',
'key': '10.1016/j.ejps.2023.106598_bib0017',
'doi-asserted-by': 'crossref',
'first-page': '101',
'DOI': '10.1002/cpt.2603',
'article-title': 'Innovative randomized phase I study and dosing regimen selection to '
'accelerate and inform pivotal COVID-19 trial of nirmatrelvir',
'volume': '112',
'author': 'Singh',
'year': '2022',
'journal-title': 'Clin. Pharmacol. Ther.'},
{ 'issue': '43',
'key': '10.1016/j.ejps.2023.106598_bib0018',
'doi-asserted-by': 'crossref',
'first-page': '18422',
'DOI': '10.1073/pnas.1010693107',
'article-title': 'Structure and mechanism of the complex between cytochrome P4503A4 and '
'ritonavir',
'volume': '107',
'author': 'Sevrioukova',
'year': '2010',
'journal-title': 'Proc. Natl. Acad. Sci. U.S.A.'},
{ 'key': '10.1016/j.ejps.2023.106598_bib0019',
'unstructured': 'WHO. https://covid19.who.int/.'}],
'container-title': 'European Journal of Pharmaceutical Sciences',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://api.elsevier.com/content/article/PII:S0928098723002282?httpAccept=text/xml',
'content-type': 'text/xml',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://api.elsevier.com/content/article/PII:S0928098723002282?httpAccept=text/plain',
'content-type': 'text/plain',
'content-version': 'vor',
'intended-application': 'text-mining'}],
'deposited': { 'date-parts': [[2023, 11, 3]],
'date-time': '2023-11-03T08:22:58Z',
'timestamp': 1698999778000},
'score': 1,
'resource': {'primary': {'URL': 'https://linkinghub.elsevier.com/retrieve/pii/S0928098723002282'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2023, 12]]},
'references-count': 18,
'alternative-id': ['S0928098723002282'],
'URL': 'http://dx.doi.org/10.1016/j.ejps.2023.106598',
'relation': {},
'ISSN': ['0928-0987'],
'subject': ['Pharmaceutical Science'],
'container-title-short': 'European Journal of Pharmaceutical Sciences',
'published': {'date-parts': [[2023, 12]]},
'assertion': [ {'value': 'Elsevier', 'name': 'publisher', 'label': 'This article is maintained by'},
{ 'value': 'A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor '
'for treatment of COVID-19, in healthy adult subjects',
'name': 'articletitle',
'label': 'Article Title'},
{ 'value': 'European Journal of Pharmaceutical Sciences',
'name': 'journaltitle',
'label': 'Journal Title'},
{ 'value': 'https://doi.org/10.1016/j.ejps.2023.106598',
'name': 'articlelink',
'label': 'CrossRef DOI link to publisher maintained version'},
{'value': 'article', 'name': 'content_type', 'label': 'Content Type'},
{ 'value': '© 2023 The Author(s). Published by Elsevier B.V.',
'name': 'copyright',
'label': 'Copyright'}],
'article-number': '106598'}
