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In Vivo Antiviral Activity of Baloxavir against PA/I38T-Substituted Influenza A Viruses at Clinically Relevant Doses

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 balo...

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Autores principales: Kuroda, Takayuki, Fukao, Keita, Yoshida, Shinpei, Oka, Ryoko, Baba, Kaoru, Ando, Yoshinori, Taniguchi, Keiichi, Noshi, Takeshi, Shishido, Takao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10222987/
https://www.ncbi.nlm.nih.gov/pubmed/37243240
http://dx.doi.org/10.3390/v15051154
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author Kuroda, Takayuki
Fukao, Keita
Yoshida, Shinpei
Oka, Ryoko
Baba, Kaoru
Ando, Yoshinori
Taniguchi, Keiichi
Noshi, Takeshi
Shishido, Takao
author_facet Kuroda, Takayuki
Fukao, Keita
Yoshida, Shinpei
Oka, Ryoko
Baba, Kaoru
Ando, Yoshinori
Taniguchi, Keiichi
Noshi, Takeshi
Shishido, Takao
author_sort Kuroda, Takayuki
collection PubMed
description 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—but clinically relevant—doses. 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.
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spelling pubmed-102229872023-05-28 In Vivo Antiviral Activity of Baloxavir against PA/I38T-Substituted Influenza A Viruses at Clinically Relevant Doses Kuroda, Takayuki Fukao, Keita Yoshida, Shinpei Oka, Ryoko Baba, Kaoru Ando, Yoshinori Taniguchi, Keiichi Noshi, Takeshi Shishido, Takao Viruses Article 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—but clinically relevant—doses. 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. MDPI 2023-05-11 /pmc/articles/PMC10222987/ /pubmed/37243240 http://dx.doi.org/10.3390/v15051154 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kuroda, Takayuki
Fukao, Keita
Yoshida, Shinpei
Oka, Ryoko
Baba, Kaoru
Ando, Yoshinori
Taniguchi, Keiichi
Noshi, Takeshi
Shishido, Takao
In Vivo Antiviral Activity of Baloxavir against PA/I38T-Substituted Influenza A Viruses at Clinically Relevant Doses
title In Vivo Antiviral Activity of Baloxavir against PA/I38T-Substituted Influenza A Viruses at Clinically Relevant Doses
title_full In Vivo Antiviral Activity of Baloxavir against PA/I38T-Substituted Influenza A Viruses at Clinically Relevant Doses
title_fullStr In Vivo Antiviral Activity of Baloxavir against PA/I38T-Substituted Influenza A Viruses at Clinically Relevant Doses
title_full_unstemmed In Vivo Antiviral Activity of Baloxavir against PA/I38T-Substituted Influenza A Viruses at Clinically Relevant Doses
title_short In Vivo Antiviral Activity of Baloxavir against PA/I38T-Substituted Influenza A Viruses at Clinically Relevant Doses
title_sort in vivo antiviral activity of baloxavir against pa/i38t-substituted influenza a viruses at clinically relevant doses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10222987/
https://www.ncbi.nlm.nih.gov/pubmed/37243240
http://dx.doi.org/10.3390/v15051154
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