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Revision as of 00:47, 24 March 2020

Favipiravir
Names
IUPAC name
6-Fluoro-3-hydroxypyrazine-2-carboxamide
Other names
T-705; Avigan; favilavir
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
UNII
  • InChI=1S/C5H4FN3O2/c6-2-1-8-5(11)3(9-2)4(7)10/h1H,(H2,7,10)(H,8,11)
    Key: ZCGNOVWYSGBHAU-UHFFFAOYSA-N
  • InChI=1/C5H4FN3O2/c6-2-1-8-5(11)3(9-2)4(7)10/h1H,(H2,7,10)(H,8,11)
    Key: ZCGNOVWYSGBHAU-UHFFFAOYAM
  • Oc1ncc(F)nc1C(=O)N
Properties
C5H4FN3O2
Molar mass 157.104 g·mol−1
Pharmacology
J05AX27 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Favipiravir, also known as T-705, Avigan, or favilavir is an antiviral drug being developed by Toyama Chemical (Fujifilm group) of Japan with activity against many RNA viruses. Like certain other experimental antiviral drugs (T-1105 and T-1106), it is a pyrazinecarboxamide derivative. In experiments conducted in animals Favipiravir has shown activity against influenza viruses, West Nile virus, yellow fever virus, foot-and-mouth disease virus as well as other flaviviruses, arenaviruses, bunyaviruses and alphaviruses.[1] Activity against enteroviruses[2] and Rift Valley fever virus has also been demonstrated.[3] Favipiravir has showed limited efficacy against Zika virus in animal studies, but was less effective than other antivirals such as MK-608.[4] The agent has also shown some efficacy against rabies,[5] and has been used experimentally in some humans infected with the virus.[6]

In February 2020, Favipiravir was being studied in China for experimental treatment of the emergent COVID-19 (novel coronavirus disease).[7][8] On March 17, Chinese officials suggested the drug had been effective in treating COVID in Wuhan and Shenzhen.[9][10]

Mechanism of action

The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase.[11] Other research suggests that favipiravir induces lethal RNA transversion mutations, producing a nonviable viral phenotype.[12] Favipiravir is a prodrug that is metabolized to its active form, favipiravir-ribofuranosyl-5'-triphosphate (favipiravir-RTP), available in both oral and intravenous formulations.[13][14] Human hypoxanthine guanine phosphoribosyltransferase (HGPRT) is believed to play a key role in this activation process.[15] Favipiravir does not inhibit RNA or DNA synthesis in mammalian cells and is not toxic to them.[1] In 2014, favipiravir was approved in Japan for stockpiling against influenza pandemics.[16] However, favipiravir has not been shown to be effective in primary human airway cells, casting doubt on its efficacy in influenza treatment.[17]

Approval status

In 2014, Japan approved Favipiravir for treating viral strains unresponsive to current antivirals.[18] Toyama Chemical initially hoped that Favipiravir would become a new influenza drug that could replace Tamiflu. However, animal experiments show the potential for teratogenic effects on fetuses, 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.[19]

In March 2015, the US Food and Drug Administration completed a Phase III clinical trial studying the safety and efficacy of Favipiravir in the treatment of influenza.[20]

On March 15, 2020 the drug was approved in China with the name Favilavir for the treatment of influenza.[21] The drug was also approved for use in clinical trials for treating coronavirus disease 2019 pneumonia.[21]

On 22 March, 2020 Italy has approved the drug for experimental use against COVID-19 and has begun conducting trials in 3 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]

Ebola virus trials

Some research has been done suggesting that in mouse models Favipiravir may have efficacy against Ebola. Its efficacy against Ebola in humans is unproven.[24][25][26] 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.[27] A clinical trial investigating the use of favipiravir against Ebola virus disease was started in Guéckédou, Guinea, during December 2014.[28] 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.[29] The trial design has been criticised by Scott Hammer and others for using only historical controls.[30] The results of this clinical trial were presented in February 2016 at the annual Conference on Retroviruses and Opportunistic Infections (CROI) by Daouda Sissoko[31] and published on March 1, 2016 in PLOS Medicine.[32]

Coronavirus disease 2019 (COVID-19)

On 17 March 2020, Chinese officials suggested that Favipiravir seemed to be effective in treating COVID-19 in Wuhan and Shenzhen.[33][34][35]

A study on 80 patients comparing it to lopinavir/ritonavir found that it significantly reduced viral clearance time to 4 days, compared to 11 days for the control group, and that 91.43% of patients had improved CT scans with few side effects. The limitation of this study is that it was not a randomized double-blinded placebo-controlled clinical trial.[36][37]

See also

References

Scholia has a profile for favipiravir (Q16934561).
  1. ^ a b Furuta Y, Takahashi K, Shiraki K, Sakamoto K, Smee DF, Barnard DL, Gowen BB, Julander JG, Morrey JD (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. PMID 19428599.
  2. ^ Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL (November 2013). "Favipiravir (T-705), a novel viral RNA polymerase inhibitor". Antiviral Research. 100 (2): 446–54. doi:10.1016/j.antiviral.2013.09.015. PMC 3880838. PMID 24084488.
  3. ^ Caroline AL, Powell DS, Bethel LM, Oury TD, Reed DS, Hartman AL (April 2014). "Broad spectrum antiviral activity of favipiravir (T-705): protection from highly lethal inhalational Rift Valley Fever". PLOS Neglected Tropical Diseases. 8 (4): e2790. doi:10.1371/journal.pntd.0002790. PMC 3983105. PMID 24722586.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  4. ^ 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): 208–11. doi:10.1007/s40506-016-0083-7. PMC 4969322. PMID 27547128.
  5. ^ 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.
  6. ^ Murphy J, Sifri CD, Pruitt R, Hornberger M, Bonds D, Blanton J, Ellison J, Cagnina RE, Enfield KB, Shiferaw M, Gigante C, Condori E, Gruszynski K, Wallace RM (January 2019). "Human Rabies - Virginia, 2017". MMWR. Morbidity and Mortality Weekly Report. 67 (5152): 1410–14. doi:10.15585/mmwr.mm675152a2. PMC 6334827. PMID 30605446.
  7. ^ Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery 2020 Feb doi:10.1038/d41573-020-00016-0
  8. ^ 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.
  9. ^ NHK World News ‘China: Avigan effective in tackling coronavirus’
  10. ^ Huaxia. "Favipiravir shows good clinical efficacy in treating COVID-19: official." Xinhuanet.com, 17 March 2020
  11. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ 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.
  13. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  14. ^ 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): 741–46. doi:10.1093/jac/dkp274. PMC 2740635. PMID 19643775.
  15. ^ 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.
  16. ^ Koons, Cynthia (7 August 2014). "Ebola Drug From Japan May Emerge Among Key Candidates". Bloomberg.com. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  17. ^ 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.
  18. ^ Hayden, Frederick (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.
  19. ^ 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". Retrieved 25 February 2014.
  20. ^ "Phase 3 Efficacy and Safety Study of Favipiravir for Treatment of Uncomplicated Influenza in Adults - T705US316". FDA. Retrieved 17 March 2020.
  21. ^ a b 陈子琰. "Potential coronavirus drug approved for marketing - Chinadaily.com.cn". www.chinadaily.com.cn. Retrieved 2020-03-21.
  22. ^ "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.
  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.
  24. ^ Gatherer D (August 2014). "The 2014 Ebola virus disease outbreak in West Africa". The Journal of General Virology. 95 (Pt 8): 1619–24. doi:10.1099/vir.0.067199-0. PMID 24795448.
  25. ^ 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.
  26. ^ 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: 153–55. doi:10.1016/j.antiviral.2014.01.012. PMID 24462697.
  27. ^ "First French Ebola patient leaves hospital". Reuters. 4 October 2016.
  28. ^ "Guinea: Clinical Trial for Potential Ebola Treatment Started in MSF Clinic in Guinea". AllAfrica – All the Time. Retrieved 28 December 2014.
  29. ^ Fink, Sheri (4 February 2015). "Ebola Drug Aids Some in a Study in West Africa". The New York Times. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  30. ^ Cohen, Jon (26 February 2015). "Results from encouraging Ebola trial scrutinized". Science. doi:10.1126/science.aaa7912. Retrieved 21 January 2016. {{cite journal}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  31. ^ "Favipiravir in Patients with Ebola Virus Disease: Early Results of the JIKI trial in Guinea | CROI Conference". croiconference.org. Retrieved 2016-03-17.
  32. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  33. ^ "Japanese flu drug 'clearly effective' in treating coronavirus, says China". The Guardian. 2020-03-18. Retrieved 2020-03-18.
  34. ^ NHK World News ‘China: Avigan effective in tackling coronavirus’
  35. ^ Huaxia. "Favipiravir shows good clinical efficacy in treating COVID-19: official." Xinhuanet.com, 17 March 2020
  36. ^ Cai, Qingxian; Yang, Minghui; Liu, Dongjing; Chen, Jun; Shu, Dan; Xia, Junxia; Liao, Xuejiao; Gu, Yuanbo; Cai, Qiue; Yang, Yang; Shen, Chenguang (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.
  37. ^ 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.
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