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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Bibliographic Details
Published in:Viruses 2023-05, Vol.15 (5), p.1154
Main Authors: Kuroda, Takayuki, Fukao, Keita, Yoshida, Shinpei, Oka, Ryoko, Baba, Kaoru, Ando, Yoshinori, Taniguchi, Keiichi, Noshi, Takeshi, Shishido, Takao
Format: Article
Language:English
Subjects:
Acids
Anesthesia
Animal models
Animals
Antiviral activity
Antiviral Agents - pharmacology
Antiviral Agents - therapeutic use
Antiviral drugs
baloxavir
Control
Disease transmission
Drug dosages
Drug Resistance, Viral
Genetic aspects
Health aspects
Health care
Humans
Infections
Influenza
Influenza A
Influenza A virus
Influenza A Virus, H1N1 Subtype
Influenza A Virus, H3N2 Subtype
Influenza viruses
Influenza, Human
Mice
Mutation
Nucleotidyltransferases
Oseltamivir
Oseltamivir - pharmacology
Oseltamivir - therapeutic use
Oxazines - pharmacology
PA/I38T
Pharmacodynamics
Pharmacokinetics
Pharmacology, Experimental
Phosphates
Plasma
Pyridines - pharmacology
Strains (organisms)
Thiepins - pharmacology
Thiepins - therapeutic use
Viruses
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Summary: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.
ISSN:1999-4915
1999-4915
DOI:10.3390/v15051154