The antiviral effects of baloxavir marboxil against influenza A virus infection in ferrets.
Animals
Antiviral Agents
/ pharmacokinetics
Body Temperature
/ drug effects
Dibenzothiepins
/ pharmacokinetics
Ferrets
Humans
Influenza A virus
/ drug effects
Influenza, Human
/ drug therapy
Microsomes
/ metabolism
Morpholines
/ pharmacokinetics
Orthomyxoviridae Infections
/ drug therapy
Oseltamivir
/ pharmacokinetics
Pyridones
/ pharmacokinetics
Triazines
/ pharmacokinetics
Viral Load
/ drug effects
baloxavir marboxil
ferrets
influenza A virus
pharmacodynamics
pharmacokinetics
Journal
Influenza and other respiratory viruses
ISSN: 1750-2659
Titre abrégé: Influenza Other Respir Viruses
Pays: England
ID NLM: 101304007
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
11
11
2019
revised:
06
05
2020
accepted:
09
05
2020
pubmed:
14
6
2020
medline:
20
7
2021
entrez:
14
6
2020
Statut:
ppublish
Résumé
Baloxavir marboxil (BXM), the oral prodrug of baloxavir acid (BXA), greatly reduces virus titers as well as influenza symptoms of uncomplicated influenza in patients. To investigate the pharmacokinetic profiles of BXA and its efficacy against influenza A virus infection in ferrets. Ferrets were dosed orally with BXM (10 and 30 mg/kg twice daily for 1 day), oseltamivir phosphate (OSP) (5 mg/kg twice daily for 2 days) or vehicle to measure the antiviral effects of BXM and OSP. The pharmacokinetic parameters of BXA was determined after single oral dosing of BXM. The maximum plasma concentrations of BXA were observed at 1.50 and 2.00 hours with the two BXM doses, which then declined with an elimination half-life of 6.91 and 4.44 hours, respectively. BXM at both doses remained detectable in the plasma in ferrets, which may be due to higher stability in liver microsomes. BXM (10 and 30 mg/kg twice daily) treatment at Day 1 post-infection (p.i.) reduced virus titers by ≥3 log10 of the 50% tissue culture infective doses by Day 2, which was significantly different compared with vehicle or OSP. Body temperature drops over time were significantly greater with BXM than with vehicle or OSP. Significant reduction in virus titers was also demonstrated when BXM was administrated after symptom onset at Day 2 p.i. compared with vehicle and OSP, although body temperature changes largely overlapped between Day 2 and Day 4. The results highlight the rapid antiviral action of BXM with post-exposure prophylaxis or therapeutic dosing in ferrets and offer support for further research on prevention of influenza virus infection and transmission.
Sections du résumé
BACKGROUND
Baloxavir marboxil (BXM), the oral prodrug of baloxavir acid (BXA), greatly reduces virus titers as well as influenza symptoms of uncomplicated influenza in patients.
OBJECTIVES
To investigate the pharmacokinetic profiles of BXA and its efficacy against influenza A virus infection in ferrets.
METHODS
Ferrets were dosed orally with BXM (10 and 30 mg/kg twice daily for 1 day), oseltamivir phosphate (OSP) (5 mg/kg twice daily for 2 days) or vehicle to measure the antiviral effects of BXM and OSP. The pharmacokinetic parameters of BXA was determined after single oral dosing of BXM.
RESULTS
The maximum plasma concentrations of BXA were observed at 1.50 and 2.00 hours with the two BXM doses, which then declined with an elimination half-life of 6.91 and 4.44 hours, respectively. BXM at both doses remained detectable in the plasma in ferrets, which may be due to higher stability in liver microsomes. BXM (10 and 30 mg/kg twice daily) treatment at Day 1 post-infection (p.i.) reduced virus titers by ≥3 log10 of the 50% tissue culture infective doses by Day 2, which was significantly different compared with vehicle or OSP. Body temperature drops over time were significantly greater with BXM than with vehicle or OSP. Significant reduction in virus titers was also demonstrated when BXM was administrated after symptom onset at Day 2 p.i. compared with vehicle and OSP, although body temperature changes largely overlapped between Day 2 and Day 4.
CONCLUSIONS
The results highlight the rapid antiviral action of BXM with post-exposure prophylaxis or therapeutic dosing in ferrets and offer support for further research on prevention of influenza virus infection and transmission.
Identifiants
pubmed: 32533654
doi: 10.1111/irv.12760
pmc: PMC7578299
doi:
Substances chimiques
Antiviral Agents
0
Dibenzothiepins
0
Morpholines
0
Pyridones
0
Triazines
0
Oseltamivir
20O93L6F9H
baloxavir
4G86Y4JT3F
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
710-719Informations de copyright
© 2020 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.
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