The mechanism of action of favipiravir is novel compared to existing influenza antivirals that primarily prevent entry and exit of the virus from cells.7 The active favipiravir-RTP selectively inhibits RNA polymerase and prevents replication of the viral genome.18 There are several hypotheses as to how favipiravir-RTP interacts with RdRp.7 Some studies have shown that when favipiravir-RTP is incorporated into a nascent RNA strand, it prevents RNA strand elongation and viral proliferation.7 Studies have also found that the presence of purine analogs can reduce favipiravir’s antiviral activity, suggesting competition between favipiravir-RTP and purine nucleosides for RdRp binding.
Although originally developed to target influenza, the RdRp catalytic domain is expected to be similar for other RNA viruses.7 This conserved RdRp catalytic domain contributes to favipiravir's broad-spectrum coverage.
Favipiravir functions as a prodrug and undergoes ribosylation and phosphorylation intracellularly to become the active favipiravir-RTP.7,10 Favipiravir-RTP binds to and inhibits RNA dependent RNA polymerase (RdRp), which ultimately prevents viral transcription and replication.
Favipiravir is extensively metabolized with metabolites excreted mainly in the urine.10 The antiviral undergoes hydroxylation primarily by aldehyde oxidase and to a lesser extent by xanthine oxidase to the inactive metabolite, T705M1.
Based on single-dose toxicity studies, the lethal dose for oral and intravenous favipiravir in mice is estimated to be >2000 mg/kg.18 In rats, the lethal dose for oral administration is >2000 mg/kg, while the lethal dose in dogs and monkeys is >1000 mg/kg.18 Symptoms of overdose appear to include but are not limited to reduced body weight, vomiting, and decreased locomotor activity.
In repeat-dose toxicity studies involving dogs, rats, and monkeys, notable findings after administration of oral favipiravir included: adverse effects on hematopoietic tissues such as decreased red blood cell (RBC) production, and increases in liver function parameters such as aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and total bilirubin, and increased vacuolization in hepatocytes.18 Testis toxicity was also noted.
Favipiravir is known to be teratogenic; therefore, administration of favipiravir should be avoided in women if pregnancy is confirmed or suspected.
Toxicity information regarding favipiravir in humans is not readily available.
Beigel J, Bray M: Current and future antiviral therapy of severe seasonal and avian influenza. Antiviral Res. 2008 Apr;78(1):91-102. doi: 10.1016/j.antiviral.2008.01.003. Epub 2008 Feb 4. [PubMed:18328578]
Hsieh HP, Hsu JT: Strategies of development of antiviral agents directed against influenza virus replication. Curr Pharm Des. 2007;13(34):3531-42. [PubMed:18220789]
Gowen BB, Wong MH, Jung KH, Sanders AB, Mendenhall M, Bailey KW, Furuta Y, Sidwell RW: In vitro and in vivo activities of T-705 against arenavirus and bunyavirus infections. Antimicrob Agents Chemother. 2007 Sep;51(9):3168-76. Epub 2007 Jul 2. [PubMed:17606691]
Sidwell RW, Barnard DL, Day CW, Smee DF, Bailey KW, Wong MH, Morrey JD, Furuta Y: Efficacy of orally administered T-705 on lethal avian influenza A (H5N1) virus infections in mice. Antimicrob Agents Chemother. 2007 Mar;51(3):845-51. Epub 2006 Dec 28. [PubMed:17194832]
Furuta Y, Takahashi K, Kuno-Maekawa M, Sangawa H, Uehara S, Kozaki K, Nomura N, Egawa H, Shiraki K: Mechanism of action of T-705 against influenza virus. Antimicrob Agents Chemother. 2005 Mar;49(3):981-6. [PubMed:15728892]
Furuta Y, Takahashi K, Fukuda Y, Kuno M, Kamiyama T, Kozaki K, Nomura N, Egawa H, Minami S, Watanabe Y, Narita H, Shiraki K: In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob Agents Chemother. 2002 Apr;46(4):977-81. [PubMed:11897578]
Furuta Y, Komeno T, Nakamura T: Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(7):449-463. doi: 10.2183/pjab.93.027. [PubMed:28769016]
Venkataraman S, Prasad BVLS, Selvarajan R: RNA Dependent RNA Polymerases: Insights from Structure, Function and Evolution. Viruses. 2018 Feb 10;10(2). pii: v10020076. doi: 10.3390/v10020076. [PubMed:29439438]
Hayden FG, Shindo N: Influenza virus polymerase inhibitors in clinical development. Curr Opin Infect Dis. 2019 Apr;32(2):176-186. doi: 10.1097/QCO.0000000000000532. [PubMed:30724789]
Madelain V, Nguyen TH, Olivo A, de Lamballerie X, Guedj J, Taburet AM, Mentre F: Ebola Virus Infection: Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in Human Efficacy Trials. Clin Pharmacokinet. 2016 Aug;55(8):907-23. doi: 10.1007/s40262-015-0364-1. [PubMed:26798032]
Nguyen TH, Guedj J, Anglaret X, Laouenan C, Madelain V, Taburet AM, Baize S, Sissoko D, Pastorino B, Rodallec A, Piorkowski G, Carazo S, Conde MN, Gala JL, Bore JA, Carbonnelle C, Jacquot F, Raoul H, Malvy D, de Lamballerie X, Mentre F: Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted. PLoS Negl Trop Dis. 2017 Feb 23;11(2):e0005389. doi: 10.1371/journal.pntd.0005389. eCollection 2017 Feb. [PubMed:28231247]
de Farias ST, Dos Santos Junior AP, Rego TG, Jose MV: Origin and Evolution of RNA-Dependent RNA Polymerase. Front Genet. 2017 Sep 20;8:125. doi: 10.3389/fgene.2017.00125. eCollection 2017. [PubMed:28979293]
Shu B, Gong P: Structural basis of viral RNA-dependent RNA polymerase catalysis and translocation. Proc Natl Acad Sci U S A. 2016 Jul 12;113(28):E4005-14. doi: 10.1073/pnas.1602591113. Epub 2016 Jun 23. [PubMed:27339134]
Nagata T, Lefor AK, Hasegawa M, Ishii M: Favipiravir: a new medication for the Ebola virus disease pandemic. Disaster Med Public Health Prep. 2015 Feb;9(1):79-81. doi: 10.1017/dmp.2014.151. Epub 2014 Dec 29. [PubMed:25544306]
Rosenke K, Feldmann H, Westover JB, Hanley PW, Martellaro C, Feldmann F, Saturday G, Lovaglio J, Scott DP, Furuta Y, Komeno T, Gowen BB, Safronetz D: Use of Favipiravir to Treat Lassa Virus Infection in Macaques. Emerg Infect Dis. 2018 Sep;24(9):1696-1699. doi: 10.3201/eid2409.180233. Epub 2018 Sep 17. [PubMed:29882740]
Delang L, Abdelnabi R, Neyts J: Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. Antiviral Res. 2018 May;153:85-94. doi: 10.1016/j.antiviral.2018.03.003. Epub 2018 Mar 7. [PubMed:29524445]
Nature Biotechnology: Coronavirus puts drug repurposing on the fast track [Link]
Pharmaceuticals and Medical Devices Agency: Avigan (favipiravir) Review Report [Link]
World Health Organization: Influenza (Avian and other zoonotic) [Link]
Favipiravir has been investigated for the treatment of life-threatening pathogens such as Ebola virus, Lassa virus, and now COVID-19.