Analgesics
Antiandrogens
Antihistamines
Azvudine
Bromhexine
Budesonide
Colchicine
Conv. Plasma
Curcumin
Famotidine
Favipiravir
Fluvoxamine
Hydroxychlor..
Ivermectin
Lifestyle
Melatonin
Metformin
Minerals
Molnupiravir
Monoclonals
Naso/orophar..
Nigella Sativa
Nitazoxanide
PPIs
Paxlovid
Quercetin
Remdesivir
Thermotherapy
Vitamins
More

Other
Feedback
Home
Top
Abstract
All xiannuoxin studies
Meta analysis
 
Feedback
Home
next
study
previous
study
c19early.org COVID-19 treatment researchXiannuoxinXiannuoxin (more..)
Melatonin Meta
Metformin Meta
Antihistamines Meta
Azvudine Meta Molnupiravir Meta
Bromhexine Meta
Budesonide Meta
Colchicine Meta Nigella Sativa Meta
Conv. Plasma Meta Nitazoxanide Meta
Curcumin Meta PPIs Meta
Famotidine Meta Paxlovid Meta
Favipiravir Meta Quercetin Meta
Fluvoxamine Meta Remdesivir Meta
Hydroxychlor.. Meta Thermotherapy Meta
Ivermectin Meta

All Studies   Meta Analysis    Recent:   

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  
  Post
  Facebook
Share
  Source   PDF   All Studies   Meta AnalysisMeta
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: zhao4wei2@hotmail.com.
This PaperXiannuoxinAll
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.2013.281053
Cde, 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.121.000801
Ich, 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/pharmaceutics13020283
Lamb, Nirmatrelvir plus ritonavir: first approval, Drugs, doi:10.1007/s40265-022-01692-5
Liu, Transporter-mediated drug-drug interactions and their significance, Adv. Exp. Med. Biol, doi:10.1007/978-981-13-7647-4_5
Ma, Li, Xie, Zhao, Yi et al., Repurposing of HIV/HCV protease inhibitors against SARS-CoV-2 3CLpro, Antiviral Res, doi:10.1016/j.antiviral.2022.105419
Miyake, Oka, Mukai, Food effect on meal administration time of pharmacokinetic profile of cilostazol, a BCS class II drug, Xenobiotica, doi:10.1080/00498254.2019.1602746
Naqvi, 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.2020.165878
Ng, Correia, Seagal, Degoey, Schrimpf et al., Antiviral drug discovery for the treatment of COVID-19 infections, Viruses, doi:10.3390/v14050961
Niederberger, Parnham, The impact of diet and exercise on drug responses, Int. J. Mol. Sci, doi:10.3390/ijms22147692
Owen, 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.abl4784
Sevrioukova, Poulos, Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir, Proc. Natl. Acad. Sci. U.S.A, doi:10.1073/pnas.1010693107
Singh, 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'}
Loading..
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
  or use drag and drop   
Submit