Favipiravir, sold under the brand name Avigan, is an antiviral medication used to treat influenza in Japan.[1] It is also being studied to treat a number of other viral infections.[1] Like the experimental antiviral drugs (T-1105 and T-1106), it is a pyrazinecarboxamide derivative.
It is being developed and manufactured by Toyama Chemical (Fujifilm group) and was approved for medical use in Japan in 2014.[2] In 2016, Fujifilm licensend API for it to Zhejiang Hisun Pharmaceutical Co. of China.[3] It became a generic drug in 2019.
Contents
1Medical use
2Side effects
3Mechanism of action
4Approval status
5Research
5.1COVID-19
5.2Ebola
5.3Other
5.4Tautomerism
6References
7External links
Medical use
Favipiravir has been approved to treat influenza in Japan.[2] It is, however, only indicated for novel influenza (strains that cause more severe disease) rather than seasonal influenza.[2] As of 2020, the probability of resistance developing appears low.[2]
Side effects
There is evidence that use during pregnancy may result in harm to the baby.[2]
Mechanism of action
The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase.[4] Other research suggests that favipiravir induces lethal RNA transversion mutations, producing a nonviable viral phenotype.[5] Favipiravir is a prodrug that is metabolized to its active form, favipiravir-ribofuranosyl-5'-triphosphate (favipiravir-RTP), available in both oral and intravenous formulations.[6][7] Human hypoxanthine guanine phosphoribosyltransferase (HGPRT) is believed to play a key role in this activation process.[8] Favipiravir does not inhibit RNA or DNA synthesis in mammalian cells and is not toxic to them.[9] In 2014, favipiravir was approved in Japan for stockpiling against influenza pandemics.[10] However, favipiravir has not been shown to be effective in primary human airway cells, casting doubt on its efficacy in influenza treatment.[11]
Approval status
The US Department of Defense developed favipiravir in partnership with MediVector, Inc. as a broad-spectrum antiviral and sponsored it through FDA Phase II and Phase III clinical trials, where it demonstrated safety in humans and efficacy against the influenza virus.[12] Despite demonstrating safety in more than 2,000 patients and showing accelerated clearance of influenza virus by 6 to 14 hours in the Phase III trials, favipiravir remains unapproved in the UK and the USA.[13] In 2014, Japan approved favipiravir for treating influenza strains unresponsive to current antivirals.[14] Toyama Chemical initially hoped that favipiravir would become a new influenza medication that could replace oseltamivir (brand name Tamiflu). However, animal experiments show the potential for teratogenic effects, and the approval of production by The Ministry of Health, Labor and Welfare was greatly delayed and the production condition is limited only in an emergency in Japan.[15]
On 15 March 2020, the drug was approved in China for the treatment of influenza.[16]
Research
COVID-19
See also: Coronavirus disease 2019 § Research, and COVID-19 drug repurposing research
In February 2020, favipiravir was being studied in China for experimental treatment of the emergent COVID-19.[17][18] Trials are also being planned in Japan.[19]
A study on 80 people in comparison to lopinavir/ritonavir found that it reduced viral clearance time, and that 91% of people had improved CT scans with few side effects. The limitation of this study was that it was not randomized double-blinded and placebo-controlled.[20][21]
The drug has been approved for use in clinical trials of coronavirus disease 2019 in China.[16] In March 2020, Italy approved the drug for experimental use against COVID-19 and has begun conducting trials in three regions most affected by the disease.[22] The Italian Pharmaceutical Agency, however, has reminded the public that the existing evidence in support of this drug is scant and preliminary.[23] There are plans to study it in three hospitals in Massachusetts, USA as of April 20, 2020.[24] As of early May 2020, a trial is starting in London, UK [25]
Ebola
Some research has been done suggesting that in mouse models Favipiravir may have efficacy against Ebola. Its efficacy against Ebola in humans is unproven.[26][27][28] During the 2014 West Africa Ebola virus outbreak, it was reported that a French nurse who contracted Ebola while volunteering for MSF in Liberia recovered after receiving a course of favipiravir.[29] A clinical trial investigating the use of favipiravir against Ebola virus disease was started in Guéckédou, Guinea, during December 2014.[30] Preliminary results showed a decrease in mortality rate in patients with low-to-moderate levels of Ebola virus in the blood, but no effect on patients with high levels of the virus, a group at a higher risk of death.[31] The trial design has been criticised for using only historical controls.[32] The results were presented in 2016 at the annual Conference on Retroviruses and Opportunistic Infections (CROI)[33] and published on 1 March 2016 in PLOS Medicine.[34]
Other
In experiments in animals favipiravir has shown activity against West Nile virus, yellow fever virus, foot-and-mouth disease virus as well as other flaviviruses, arenaviruses, bunyaviruses and alphaviruses.[9] Activity against enteroviruses[35] and Rift Valley fever virus has also been demonstrated.[36] Favipiravir has showed limited efficacy against Zika virus in animal studies, but was less effective than other antivirals such as MK-608.[37] The agent has also shown some efficacy against rabies,[38] and has been used experimentally in some humans infected with the virus.[39]
Tautomerism
The capacity of favipiravir to exist in a keto-like tautomeric form has been investigated computationally. It was found that the enol-like form was substantially more stable in aqueous solution than the keto-like form, meaning that Favipiravir likely exists almost exclusively in the enol-like form in aqueous solution. However these findings were caveated with the need to confirm this experimentally.[40]
Enol-like tautomeric form
Keto-like tautomeric form
References
^ abDu YX, Chen XP (April 2020). "Favipiravir: pharmacokinetics and concerns about clinical trials for 2019-nCoV infection". Clinical Pharmacology and Therapeutics. doi:10.1002/cpt.1844. PMID 32246834.
^ abcdeShiraki K, Daikoku T (February 2020). "Favipiravir, an anti-influenza drug against life-threatening RNA virus infections". Pharmacology & Therapeutics: 107512. doi:10.1016/j.pharmthera.2020.107512. PMC 7102570. PMID 32097670.
^EJ Lane (June 22, 2016). "Fujifilm in Avigan API license with Zhejiang Hisun Pharmaceuticals". Retrieved April 20, 2020.
^Jin Z, Smith LK, Rajwanshi VK, Kim B, Deval J (2013). "The ambiguous base-pairing and high substrate efficiency of T-705 (Favipiravir) Ribofuranosyl 5'-triphosphate towards influenza A virus polymerase". PLOS One. 8 (7): e68347. Bibcode:2013PLoSO...868347J. doi:10.1371/journal.pone.0068347. PMC 3707847. PMID 23874596.
^Baranovich T, Wong SS, Armstrong J, Marjuki H, Webby RJ, Webster RG, Govorkova EA (April 2013). "T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro". Journal of Virology. 87 (7): 3741–51. doi:10.1128/JVI.02346-12. PMC 3624194. PMID 23325689.
^Guedj J, Piorkowski G, Jacquot F, Madelain V, Nguyen TH, Rodallec A, et al. (March 2018). "Antiviral efficacy of favipiravir against Ebola virus: A translational study in cynomolgus macaques". PLOS Medicine. 15 (3): e1002535. doi:10.1371/journal.pmed.1002535. PMC 5870946. PMID 29584730.
^Smee DF, Hurst BL, Egawa H, Takahashi K, Kadota T, Furuta Y (October 2009). "Intracellular metabolism of favipiravir (T-705) in uninfected and influenza A (H5N1) virus-infected cells". The Journal of Antimicrobial Chemotherapy. 64 (4): 741–6. doi:10.1093/jac/dkp274. PMC 2740635. PMID 19643775.
^Naesens L, Guddat LW, Keough DT, van Kuilenburg AB, Meijer J, Vande Voorde J, Balzarini J (October 2013). "Role of human hypoxanthine guanine phosphoribosyltransferase in activation of the antiviral agent T-705 (favipiravir)". Molecular Pharmacology. 84 (4): 615–29. doi:10.1124/mol.113.087247. PMID 23907213.
^ abFuruta Y, Takahashi K, Shiraki K, Sakamoto K, Smee DF, Barnard DL, et al. (June 2009). "T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections". Antiviral Research. 82 (3): 95–102. doi:10.1016/j.antiviral.2009.02.198. PMC 7127082. PMID 19428599.
^Koons C (7 August 2014). "Ebola Drug From Japan May Emerge Among Key Candidates". Bloomberg.com.
^Yoon JJ, Toots M, Lee S, Lee ME, Ludeke B, Luczo JM, et al. (August 2018). "Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses". Antimicrobial Agents and Chemotherapy. 62 (8): e00766–18. doi:10.1128/AAC.00766-18. PMC 6105843. PMID 29891600.
^"MediVector Completes Patient Enrollment In Two Phase 3 Studies Of Favipiravir For Influenza". BioSpace. Retrieved 5 May 2020.
^Lumby, Casper (3 March 2020). "Favipiravir and Zanamivir Cleared Infection with Influenza B in a Severely Immunocompromised Child". Clinical Infectious Diseases. Retrieved 5 May 2020.
^Hayden FG, Shindo N (April 2019). "Influenza virus polymerase inhibitors in clinical development". Current Opinion in Infectious Diseases. 32 (2): 176–186. doi:10.1097/QCO.0000000000000532. PMC 6416007. PMID 30724789.
^条件付き承認で普及に足かせ 富山化学インフル薬の"無念" (in Japanese). Retrieved 25 February 2014.
^ abYangfei Z. "Potential coronavirus drug approved for marketing". Chinadaily.com.cn. Retrieved 2020-03-21.
^Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery 2020 February doi:10.1038/d41573-020-00016-0
^Brief –Corrected – Zhejiang Hisun Pharma gets approval for clinical trial to test flu drug Favipiravir for pneumonia caused by new coronavirus. Reuters Healthcare, February 16, 2020.
^"Fujifilm Announces the Start of a Phase III Clinical Trial of Influenza Antiviral Drug Avigan (favipiravir) on COVID-19 in Japan and Commits to Increasing Production". Drugs.com. Retrieved 12 April 2020.
^Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, et al. (2020-03-18). "Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study". Engineering. doi:10.1016/j.eng.2020.03.007. ISSN 2095-8099.
^Dong L, Hu S, Gao J (2020). "Discovering drugs to treat coronavirus disease 2019 (COVID-19)". Drug Discoveries & Therapeutics. 14 (1): 58–60. doi:10.5582/ddt.2020.01012. PMID 32147628.
^"Coronavirus, il Veneto sperimenta l'antivirale giapponese Favipiravir. Ma l'Aifa: "Ci sono scarse evidenze scientifiche su efficacia"". Il Fatto Quotidiano (in Italian). 2020-03-22. Retrieved 2020-03-23.
^"AIFA precisa, uso favipiravir per COVID-19 non autorizzato in Europa e USA, scarse evidenze scientifiche sull'efficacia". aifa.gov.it (in Italian). Retrieved 2020-03-23.
^"Favipiravir to Treat COVID-19: Q&A with Boris Juelg, MD, PhD". Mass General Advances in Motion. Retrieved 29 April 2020.
^"UK coronavirus patients set to trial 'promising' Japanese-made drug". London Evening Standard. Retrieved May 2, 2020.
^Gatherer D (August 2014). "The 2014 Ebola virus disease outbreak in West Africa". The Journal of General Virology. 95 (Pt 8): 1619–1624. doi:10.1099/vir.0.067199-0. PMID 24795448.
^Oestereich L, Lüdtke A, Wurr S, Rieger T, Muñoz-Fontela C, Günther S (May 2014). "Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model". Antiviral Research. 105: 17–21. doi:10.1016/j.antiviral.2014.02.014. PMID 24583123.
^Smither SJ, Eastaugh LS, Steward JA, Nelson M, Lenk RP, Lever MS (April 2014). "Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model". Antiviral Research. 104: 153–5. doi:10.1016/j.antiviral.2014.01.012. PMID 24462697.
^"First French Ebola patient leaves hospital". Reuters. 4 October 2016.
^"Guinea: Clinical Trial for Potential Ebola Treatment Started in MSF Clinic in Guinea". AllAfrica – All the Time. Retrieved 28 December 2014.
^Fink S (4 February 2015). "Ebola Drug Aids Some in a Study in West Africa". The New York Times.
^Cohen J (26 February 2015). "Results from encouraging Ebola trial scrutinized". Science. doi:10.1126/science.aaa7912. Retrieved 21 January 2016.
^"Favipiravir in Patients with Ebola Virus Disease: Early Results of the JIKI trial in Guinea | CROI Conference". croiconference.org. Retrieved 2016-03-17.
^Sissoko D, Laouenan C, Folkesson E, M'Lebing AB, Beavogui AH, Baize S, et al. (March 2016). "Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea". PLOS Medicine. 13 (3): e1001967. doi:10.1371/journal.pmed.1001967. PMC 4773183. PMID 26930627.
^Mumtaz N, van Kampen JJ, Reusken CB, Boucher CA, Koopmans MP (2016). "Zika Virus: Where Is the Treatment?". Current Treatment Options in Infectious Diseases. 8 (3): 208–211. doi:10.1007/s40506-016-0083-7. PMC 4969322. PMID 27547128.
^Yamada K, Noguchi K, Komeno T, Furuta Y, Nishizono A (April 2016). "Efficacy of Favipiravir (T-705) in Rabies Postexposure Prophylaxis". The Journal of Infectious Diseases. 213 (8): 1253–61. doi:10.1093/infdis/jiv586. PMC 4799667. PMID 26655300.
…patients in nonrandomized trials. Many of these therapies (eg, convalescent plasma and whole blood, favipiravir) were found to be of no or unclear benefit and are no longer being investigated . Only one novel…
…agents that target the IL-6 pathway and are also being evaluated in clinical trials. Favipiravir – Favipiravir is an RNA polymerase inhibitor that is available in some Asian countries for treatment of…
…plasma for patients with severe or life-threatening COVID-19. Other investigational agents include favipiravir, interferon beta, lopinavir-ritonavir, and combination therapy with hydroxychloroquine plus azithromycin…
…treatment of patients with SFTS has been described, but there is no convincing therapeutic effect . Favipiravir, a pyrazine derivative, has stronger antiviral activity than that of ribavirin in vitro and in…
…neuropsychiatric, hematologic, gastrointestinal, and/or autoimmune complications. A fourth drug, favipiravir, has failed to show efficacy in animal models of rabies and is not approved for human use in most …
English Journal
Effectiveness of favipiravir (T-705) against wild-type and oseltamivir-resistant influenza B virus in mice.
Fang QQ, Huang WJ, Li XY, Cheng YH, Tan MJ, Liu J, Wei HJ, Meng Y, Wang DY.
Virology. 2020 Jun;545()1-9.
The emergence of resistant mutants to the wildly used neuraminidase inhibitors (NAIs) makes the development of novel drugs necessary. Favipiravir (T-705) is one of the RNA-dependent RNA polymerase (RdRp) inhibitors developed in recent years. To examine the efficacy of T-705 against influenza B virus
Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice.
Kiso M, Yamayoshi S, Kawaoka Y.
Communications biology. 2020 May;3(1)219.
Prolonged treatment of immunocompromised influenza patients with viral neuraminidase (NA) inhibitors is required, because the immune system of such patients fails to eradicate the viruses. Here, we attempted to eradicate influenza virus from the respiratory organs of nude mice, which is a model of i
Drug discoveries & therapeutics. 2020 May;14(2)67-72.
The virus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is currently affecting more than 200 countries and territories worldwide. It has been declared as pandemic by World Health Organization (WHO) and the whole world is suffering from corona virus disease 2019 (COVID-19). Currently,