{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T15:30:05Z","timestamp":1782487805753,"version":"3.54.5"},"reference-count":28,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T00:00:00Z","timestamp":1683763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shionogi &amp; Co., Ltd."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Although the prevalence of polymerase acidic (PA)\/I38T strains of influenza virus with reduced susceptibility to baloxavir acid is low, there is a possibility of emergence under selective pressure. Furthermore, the virus may be transmitted between humans. We investigated the in vivo efficacy of baloxavir acid and oseltamivir phosphate against influenza A subtypes H1N1, H1N1pdm09, and H3N2, with PA\/I38T substitution, at doses simulating human plasma concentrations. A pharmacokinetic\/pharmacodynamic analysis was performed to strengthen the validity of the findings and the applicability in a clinical setting. Although the antiviral effect of baloxavir acid was attenuated in mice infected with PA\/I38T-substituted viral strains compared with the wild type (WT), baloxavir acid significantly reduced virus titers at higher\u2014but clinically relevant\u2014doses. The virus titer reduction with baloxavir acid (30 mg\/kg subcutaneous single dose) was comparable to that of oseltamivir phosphate (5 mg\/kg orally twice daily) against H1N1 and H1N1pdm09 PA\/I38T strains in mice, as well as the H3N2 PA\/I38T strain in hamsters. Baloxavir acid demonstrated an antiviral effect against PA\/I38T-substituted strains, at day 6, with no further viral rebound. In conclusion, baloxavir acid demonstrated dose-dependent antiviral effects comparable to that of oseltamivir phosphate, even though the degree of lung virus titer reduction was diminished in animal models infected with PA\/I38T-substituted strains.<\/jats:p>","DOI":"10.3390\/v15051154","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T04:29:01Z","timestamp":1683779341000},"page":"1154","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["In Vivo Antiviral Activity of Baloxavir against PA\/I38T-Substituted Influenza A Viruses at Clinically Relevant Doses"],"prefix":"10.3390","volume":"15","author":[{"given":"Takayuki","family":"Kuroda","sequence":"first","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keita","family":"Fukao","sequence":"additional","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinpei","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoko","family":"Oka","sequence":"additional","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Baba","sequence":"additional","affiliation":[{"name":"Shionogi TechnoAdvance Research, Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Ando","sequence":"additional","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4694-2146","authenticated-orcid":false,"given":"Keiichi","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Noshi","sequence":"additional","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2549-0945","authenticated-orcid":false,"given":"Takao","family":"Shishido","sequence":"additional","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1186\/s13054-019-2491-9","article-title":"Influenza virus-related critical illness: Prevention, diagnosis, treatment","volume":"23","author":"Chow","year":"2019","journal-title":"Crit. Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.3389\/fmicb.2019.01327","article-title":"Overview of current therapeutics and novel candidates against influenza, respiratory syncytial virus, and middle east respiratory syndrome coronavirus infections","volume":"10","author":"Behzadi","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3389\/fmed.2019.00109","article-title":"Drugs for Influenza Treatment: Is There Significant News?","volume":"6","author":"Principi","year":"2019","journal-title":"Front. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1001\/jama.283.8.1016","article-title":"Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: A randomized controlled trial. US Oral Neuraminidase Study Group","volume":"283","author":"Treanor","year":"2000","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3403","DOI":"10.1128\/AAC.45.12.3403-3408.2001","article-title":"Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants","volume":"45","author":"Gubareva","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.antiviral.2018.10.008","article-title":"In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit","volume":"160","author":"Noshi","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1056\/NEJMoa1716197","article-title":"Baloxavir marboxil for uncomplicated influenza in adults and adolescents","volume":"379","author":"Hayden","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1016\/S1473-3099(20)30004-9","article-title":"Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): A randomised, placebo-controlled, phase 3 trial","volume":"20","author":"Ison","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1093\/jac\/dky462","article-title":"Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection","volume":"74","author":"Fukao","year":"2019","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3466","DOI":"10.1038\/s41598-019-39683-4","article-title":"Inhibition of avian-origin influenza A(H7N9) virus by the novel cap-dependent endonuclease inhibitor baloxavir marboxil","volume":"9","author":"Taniguchi","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1093\/jac\/dkaa393","article-title":"Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection","volume":"76","author":"Ando","year":"2021","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Taniguchi, K., Ando, Y., Kobayashi, M., Toba, S., Nobori, H., Sanaki, T., Noshi, T., Kawai, M., Yoshida, R., and Sato, A. (2022). Characterization of the in vitro and in vivo efficacy of baloxavir marboxil against H5 highly pathogenic avian influenza virus infection. Viruses, 14.","DOI":"10.20944\/preprints202111.0184.v2"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.3201\/eid2510.190607","article-title":"Susceptibility of Influenza A, B, C, and D Viruses to Baloxavir(1)","volume":"25","author":"Mishin","year":"2019","journal-title":"Emerg. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9633","DOI":"10.1038\/s41598-018-27890-4","article-title":"Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil","volume":"8","author":"Omoto","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1800666","DOI":"10.2807\/1560-7917.ES.2019.24.3.1800666","article-title":"Assessing baloxavir susceptibility of influenza viruses circulating in the United States during the 2016\/17 and 2017\/18 seasons","volume":"24","author":"Gubareva","year":"2019","journal-title":"Eurosurveillance"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1800698","DOI":"10.2807\/1560-7917.ES.2019.24.3.1800698","article-title":"Detection of influenza A(H3N2) viruses exhibiting reduced susceptibility to the novel cap-dependent endonuclease inhibitor baloxavir in Japan, December 2018","volume":"24","author":"Takashita","year":"2019","journal-title":"Eurosurveillance"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41564-019-0609-0","article-title":"Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets","volume":"5","author":"Imai","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lee, L.Y., Zhouc, J., Koszalkac, P., Frisec, R., Farrukeec, R., Babac, K., Miahc, S., Shishidoc, T., Galianoc, M., and Hashimotoc, T. (2021). Evaluating the fitness of PA\/I38T-substituted influenza A viruses with reduced baloxavir susceptibility in a competitive mixtures ferret model. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009527"},{"key":"ref_19","unstructured":"WHO (2023, March 14). Recommended Composition of Influenza Virus Vaccines for Use in the 2021\u20132022 Northern Hemisphere Influenza Season. Available online: https:\/\/cdn.who.int\/media\/docs\/default-source\/influenza\/who-influenza-recommendations\/vcm-northern-hemisphere-recommendation-2021-2022\/202102_recommendation.pdf?sfvrsn=2af603d8_12&download=true."},{"key":"ref_20","unstructured":"WHO (2023, March 14). Recommended Composition of Influenza Virus Vaccines for Use in the 2020 Southern Hemisphere Influenza Season. Available online: https:\/\/cdn.who.int\/media\/docs\/default-source\/influenza\/who-influenza-recommendations\/vcm-southern-hemisphere-recommendation-2020\/201909-recommendation.pdf?sfvrsn=f34905d9_13&download=true."},{"key":"ref_21","unstructured":"WHO (2023, March 14). Recommended Composition of Influenza Virus Vaccines for Use in the 2020\u20132021 Northern Hemisphere Influenza Season. Available online: https:\/\/cdn.who.int\/media\/docs\/default-source\/influenza\/who-influenza-recommendations\/vcm-northern-hemisphere-recommendation-2020-2021\/202002-recommendation.pdf?sfvrsn=6868e7b3_21&download=true."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/irv.12821","article-title":"Comprehensive assessment of amino acid substitutions in the trimeric RNA polymerase complex of influenza A virus detected in clinical trials of baloxavir marboxil","volume":"15","author":"Hashimoto","year":"2021","journal-title":"Influenza Other Respir. Viruses"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.3201\/eid2511.190757","article-title":"Human-to-human transmission of influenza A(H3N2) virus with reduced susceptibility to baloxavir, Japan, February 2019","volume":"25","author":"Takashita","year":"2019","journal-title":"Emerg. Infect. Dis."},{"key":"ref_24","first-page":"346","article-title":"Treatment-emergent influenza variant viruses with reduced baloxavir susceptibility: Impact on clinical and virologic outcomes in uncomplicated influenza","volume":"221","author":"Uehara","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.jiac.2019.12.002","article-title":"Duration of fever and PA\/I38X-substituted virus emergence in patients treated with baloxavir in the 2018\u20132019 influenza season","volume":"26","author":"Ikematsu","year":"2020","journal-title":"J. Infect. Chemother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"104951","DOI":"10.1016\/j.antiviral.2020.104951","article-title":"Duration of fever and symptoms in children after treatment with baloxavir marboxil and oseltamivir during the 2018\u20132019 season and detection of variant influenza a viruses with polymerase acidic subunit substitutions","volume":"183","author":"Saito","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1016\/j.xphs.2018.12.005","article-title":"Population pharmacokinetic and exposure-response analyses of baloxavir marboxil in adults and adolescents including patients with influenza","volume":"108","author":"Koshimichi","year":"2019","journal-title":"J. Pharm. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"i5","DOI":"10.1093\/jac\/dki018","article-title":"Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic","volume":"55","author":"Ward","year":"2005","journal-title":"J. Antimicrob. Chemother."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/5\/1154\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:32:50Z","timestamp":1760124770000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/5\/1154"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,11]]},"references-count":28,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["v15051154"],"URL":"https:\/\/doi.org\/10.3390\/v15051154","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,11]]}}}