Favipiravir

Favipiravir- properties, uses, mechanism, side effects, COVID-19

Last Updated on June 25, 2020 by Sagar Aryal

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What is Favipiravir?

Favipiravir is an antiviral drug that was developed for the treatment of resistant influenza virus in Japan. Its biochemical name is 6-fluoro-3-hydroxy-2-pyrazinecarboxamid; with the generic names being Abigan or Avigan. Favipiravir is a modified pyrazine analog (purine nucleoside analog or a derivative of pyrazine carboxamide), initially approved for the treatment of influenza that was resistant to oseltamivir and zanamivir therapies.

  • The drug mechanism involves inhibition of RNA-dependent RNA polymerase enzyme which is used in transcription and replication of the viral genome.
  • Favipiravir has also been investigated for use in that treatment of viral hemorrhagic fever (Ebola), Lassa virus, and currently, its on trial for treatment of COVID-19.
  • The drug was developed in Japan by Toyama Chemical Co., Ltd for the treatment of Influenza A and B and approved for use only in Japan.
  • Current research is being done for treatment fo other RNA viral infections such as Ebola, Lassa virus, Nipah virus, and the novel coronavirus, SARS-CoV-2.

Favipiravir

Image created using biorender.com

Properties and pharmacodynamics of Favipiravir

  • Favipiravir has a molecular weight of 157.1 g/mol
  • It has a high absorption rate of 97.6%
  • It has a plasma protein-binding activity of 54%; with 65% binding to serum albumin and 6.5% binding to the alpha-acid glycoproteins.
  • Favipiravir is a prodrug which metabolizes by ribosylation and phosphorylation forming an active form known as the favipiravir-ribofuranosyl-5′-triphosphate, (favipiravir-RTP).
  • Favipiravir metabolites are eliminated by renal excretion.

Uses of Favipiravir

  • Treatment of Influenza A and B viruses
  • Treatment of Ebola virus (on trial)
  • Treatment of Yellow fever (on trial)
  • Treatment of Nipah virus (on trial)

Mechanism of Action of Favipiravir

The active form, favipiravir-RTP binds to and inhibits the RNA-dependent RNA polymerase (RdRp), preventing viral transcription and replication.

Research into the mechanism of action of favipiravir has been related to hypothetical processes that may be generated by the prodrug after metabolism to its active form such as:

  • Incorporation of favipiravir-RTP into a newly formed RNA strand preventing its elongation and proliferation of the viral genome.
  • Competitive binding of RNA-dependent RNA polymerase by the favipiravir-RTP and purine nucleosides, which ultimately affects viral replication and transcription.

Side effects of favipiravir

  • Reduced body weight
  • Vomiting
  • Reduced locomotive activity
  • Adverse side effects include:
    • decreased production of red blood cells
    • an increased liver function such as the production of aspartate aminotransferase, alkaline phosphatase, alanine aminotransferase, and total albumin
    • increased vacuolization in hepatocytes
    • It is teratogenic meaning, it can cause congenital defects and therefore should be avoided in pregnant women.

Contraindications of Favipiravir

The major and commonly known contraindication of favipiravir is its effect on pregnant and locating women, which has been associated with embryonic deaths and teratogenicity.

Drug interactions with Favipiravir

Some of the drugs that interact with favipiravir have shown to have the effect of reduced or increased metabolism, reduced or increased excitation, and reduced or increased serum concentration when combined with favipiravir.

Some examples include:

  • Acyclovir – a nucleoside analog antiviral used to treat herpes simplex, Varicella zoster, herpes zoster, herpes labialis, and acute herpetic keratitis; favipiravir decrease the rate of exception of acyclovir when combined.
  • Aminophenazone is a pyrazolone with analgesic, anti-inflammatory, and antipyretic properties that carries a risk of agranulocytosis; favipiravir decreases its metabolism in the body when consumed together.
  • Apomorphine drug used t increase movement in persons with Parkinson’s disease; its metabolism is reduced when consumed with favipiravir
  • Benzylpenicillin antibiotic for the treatment of bacterial infection shows reduced excretion when consumed with favipiravir.
  • Chloroquine an antimalarial and anti-inflammatory drug shows a decrease in its metabolism when combined with favipiravir.
  • Other drugs that interact with favipiravir are Diclofenac, digoxin, doxorubicin, edoxaban, fluorouracil, ibuprofen, hydrocortisone, hydroxychloroquine.

Research on Faviparivir

  • Favipiravir is a broad-spectrum antiviral drug with the evidence-based research on its efficacy of anti-viral activity in several human RNA viruses such as influenza virus, Nipah virus, Viral Hemorrhagic fever (Ebola virus) Lassa virus, and rabies.
  • It has also been used in the treatment of severe fever caused by thrombocytopenia syndrome.
  • This treatment has shown effectiveness with no cases of developed resistance to favipiravir, reported.
  • In 2016, favipiravir was used in the treatment of the Ebola virus and it showed a decrease in mortality for patients with low and moderate viral load in blood but no effect was noted in patients with high levels of viral load with high risks of death.
  • Other studies for other viral infections such as the Zika virus, Yellow fever, West Nile virus, infections of bunyaviruses, alphaviruses, arenaviruses are ongoing.

Favipiravir and COVID-19

  • As of recent, favipiravir was one of the experimental drugs on trial for COVID-19,  a viral infection caused by the novel coronavirus, SARS-CoV-2. so far the drug has shown an 80% efficacy and its moving to the third phase of the trial against COVID-19.
  • The underlying mechanism of the favipiravir is the metabolization of its active form which inhibits the action of RNA-dependent RNA polymerase stopping transcription and replication.
  • The initial study was done in Japan and China in February 2020 with evidence of the reduced time of viral clearance. (https://www.pharmaceutical-technology.com/news/fujifilm-favipiravir-covid-19/)
  • It has been approved for use in the treatment of COVID-19 in China, Japan, Italy, and Russia as of June 11, 2020.

Mechanism of Action of Favipiravir

Figure: Favipiravir: Potential Repurposed Drug Candidate for COVID-19. Image created using biorender.com

References and sources

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