In Vitro Combinations of Baloxavir Acid and Other Inhibitors against Seasonal Influenza A Viruses

Viruses. 2020 Oct 8;12(10):1139. doi: 10.3390/v12101139.


Two antiviral classes, the neuraminidase inhibitors (NAIs) and polymerase inhibitors (baloxavir marboxil and favipiravir) can be used to prevent and treat influenza infections during seasonal epidemics and pandemics. However, prolonged treatment may lead to the emergence of drug resistance. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we evaluated in vitro combinations of baloxavir acid (BXA) and other approved drugs against influenza A(H1N1)pdm09 and A(H3N2) subtypes. The determination of an effective concentration inhibiting virus cytopathic effects by 50% (EC50) for each drug and combination indexes (CIs) were based on cell viability. CompuSyn software was used to determine synergism, additivity or antagonism between drugs. Combinations of BXA and NAIs or favipiravir had synergistic effects on cell viability against the two influenza A subtypes. Those effects were confirmed using a physiological and predictive ex vivo reconstructed human airway epithelium model. On the other hand, the combination of BXA and ribavirin showed mixed results. Overall, BXA stands as a good candidate for combination with several existing drugs, notably oseltamivir and favipiravir, to improve in vitro antiviral activity. These results should be considered for further animal and clinical evaluations.

Keywords: A(H1N1) virus; A(H3N2) virus; baloxavir; combination; human airway epithelium; influenza; neuraminidase inhibitors; polymerase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acids, Carbocyclic / pharmacology
  • Amides / pharmacology
  • Animals
  • Antiviral Agents / pharmacology
  • Cell Line
  • Dibenzothiepins / pharmacology
  • Dogs
  • Drug Combinations
  • Drug Resistance, Viral / drug effects
  • Drug Synergism
  • Guanidines / pharmacology
  • Influenza A Virus, H1N1 Subtype / drug effects*
  • Influenza A Virus, H3N2 Subtype / drug effects*
  • Madin Darby Canine Kidney Cells
  • Morpholines / pharmacology
  • Neuraminidase / antagonists & inhibitors*
  • Nucleic Acid Synthesis Inhibitors / pharmacology*
  • Orthomyxoviridae Infections / drug therapy*
  • Oseltamivir / pharmacology
  • Pyrazines / pharmacology
  • Pyridones / pharmacology
  • Ribavirin / pharmacology
  • Triazines / pharmacology
  • Viral Proteins / antagonists & inhibitors
  • Virus Replication / drug effects
  • Zanamivir / pharmacology


  • Acids, Carbocyclic
  • Amides
  • Antiviral Agents
  • Dibenzothiepins
  • Drug Combinations
  • Guanidines
  • Morpholines
  • Nucleic Acid Synthesis Inhibitors
  • Pyrazines
  • Pyridones
  • Triazines
  • Viral Proteins
  • Oseltamivir
  • Ribavirin
  • baloxavir
  • Neuraminidase
  • favipiravir
  • Zanamivir
  • peramivir

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