Favipiravir

Favipiravir
Names
Trade namesAvigan (アビガン, Abigan), Avifavir,[1] Areplivir,[2] others
Other namesT-705, favipira, favilavir
IUPAC name
  • 6-fluoro-3-hydroxypyrazine-2-carboxamide
Clinical data
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		By mouth
Legal
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
  • 259793-96-9
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ATC code
Chemical and physical data
FormulaC5H4FN3O2
Molar mass157.104 g·mol−1
3D model (JSmol)
SMILES
  • C1=C(N=C(C(=O)N1)C(=O)N)F
InChI
  • 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

Favipiravir, sold under the brand name Avigan among others,[3] is an antiviral medication used to treat influenza in Japan.[4] It is also being studied to treat a number of other viral infections, including SARS-CoV-2.[4] Like the experimental antiviral drugs T-1105 and T-1106, it is a pyrazinecarboxamide derivative.[5]

It is being developed and manufactured by Toyama Chemical (a subsidiary of Fujifilm) and was approved for medical use in Japan in 2014.[6] In 2016, Fujifilm licensed it to Zhejiang Hisun Pharmaceutical Co.[7] It became a generic drug in 2019.

Medical use

Favipiravir has been approved to treat influenza in Japan.[6] It is, however, only indicated for novel influenza (strains that cause more severe disease) rather than seasonal influenza.[6][8] As of 2020, the probability of resistance developing appears low.[6]

Side effects

There is evidence that use during pregnancy may result in harm to the baby.[6] Teratogenic and embryotoxic effects were shown on four animal species.[6][9]

Mechanism of action

The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase.[10] Favipiravir is a prodrug that is metabolized to its active form, favipiravir-ribofuranosyl-5'-triphosphate (favipiravir-RTP), available in both oral and intravenous formulations.[11][12] In 2014, favipiravir was approved in Japan for stockpiling against influenza pandemics.[13] However, favipiravir has not been shown to be effective in primary human airway cells, casting doubt on its efficacy in influenza treatment.[14]

Favipiravir-RTP is a nucleoside analogue. It mimics both guanosine and adenosine for the viral RdRP. Incorporating two such bases in a row stops primer extension, although it is unclear how as of 2013.[10]

  • Replication cycle of influenza and sites of action of anti-influenza drugs
    Replication cycle of influenza and sites of action of anti-influenza drugs
  • Favipiravir ribofuranosyl triphosphate, the active form inside the body
    Favipiravir ribofuranosyl triphosphate, the active form inside the body

Society and culture

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.[15] Despite demonstrating safety in more than 2,000 patients and showing accelerated clearance of influenza virus by 6 to 14 hours in the unpublished Phase III trials, favipiravir remains unapproved in the UK and the USA.[16] In 2014, Japan approved favipiravir for treating influenza strains unresponsive to current antivirals.[17] 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.[18]

Despite limited data on efficacy, as of March 2021 favipiravir is widely prescribed for outpatient treatment of mild to moderate COVID-19 in Egypt,[19] Hungary[20] and Serbia.[21] Patients are required to sign a consent form before obtaining the drug.

Brand names

Favipiravir Tablets 800 mg from India.

Favipiravir is sold under the brand names Avigan (アビガン, Abigan), Avifavir,[1] Avipiravir,[22] Areplivir,[2] FabiFlu,[23] Favipira,[24] Reeqonus,[25][26] and Qifenda.

Research

COVID-19

See also: Coronavirus disease 2019 § Research, and COVID-19 drug repurposing research § Favipiravir

Favipiravir, as an antiviral drug, has been authorized for treating COVID-19 in several countries including Japan, Russia, Serbia, Turkey, India, and Thailand, under emergency provisions.[27][28][29][30] A rapid meta-review in September 2020 (analyzing four studies) noted that the drug led to clinical and radiological improvements; however, no reduction in mortality or differences in oxygen-support requirement were observed and more rigorous studies were sought.[31][32]

As of May 2021, large-cohort clinical trials are underway.[33]

Ebola

Research in 2014, suggested that favipiravir may have efficacy against Ebola based on studies in mouse models; efficacy in humans was unaddressed.[34][35][36]

During the 2014 West Africa Ebola virus outbreak, a French nurse who contracted Ebola while volunteering for Médecins Sans Frontières (MSF) in Liberia reportedly recovered after receiving a course of favipiravir.[37] A clinical trial investigating the use of favipiravir against Ebola virus disease began in Guéckédou, Guinea, in December 2014.[38] Preliminary results presented in 2016 at the Conference on Retroviruses and Opportunistic Infections (CROI), later published, showed a decrease in mortality in patients with low-to-moderate levels of virus in blood, but no effect on patients with high levels (the group at a higher risk of death).[39][40][41] The trial design was concomitantly criticised for using only historical controls.[42]

Nipah

Nipah virus is a causative agent of outbreaks of encephalitis with pneumonia and has a high case fatality rate. The first outbreak occurred in Malaysia-Singapore, related to contact with pigs in slaughterhouses and an outbreak in Philippines related to slaughter of horses, most other outbreaks have affected India and Bangladesh. in Bangladesh outbreaks are often associated with consumption of raw date palm sap contaminated by saliva and urine of fruit bats.[43] In a study published in the Scientific Reports, Syrian hamster model for Nipah virus infection was used, which closely mirrors most aspects of human disease, such as widespread vasculitis, pneumonia, and encephalitis. The hamsters were infected with a lethal dose of 104 PFU NiV-M via the intraperitoneal (i.p.) route similar to previous studies and treatment was initiated immediately after infection. Favipiravir was administered twice daily via the peroral (p.o.) route for 14 days. The treated hamsters displayed 100% survival and no obvious morbidity after lethal NiV challenge, whereas all the control cases died of severe disease.[44]

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.[45] Activity against enteroviruses[46] and Rift Valley fever virus has also been demonstrated.[47] Favipiravir has showed limited efficacy against Zika virus in animal studies, but was less effective than other antivirals such as MK-608.[48] The agent has also shown some efficacy against rabies,[49] and has been used experimentally in some humans infected with the virus.[50]

Tautomerism

The possible tautomerism of favipiravir has been investigated computationally[51] and experimentally.[52] It was found that the enol-like form was substantially more stable in organic solvents than the keto-like form, meaning that Favipiravir likely exists almost exclusively in the enol-like form. In aqueous solution the keto-like tautomer is substantially stabilized due to the specific interaction with the water molecules. Upon protonation the keto form is switched on.

  • Enol-like tautomeric form
    Enol-like tautomeric form
  • Keto-like tautomeric form
    Keto-like tautomeric form

References

  1. 1 2 "Avifavir". Russian drug reference. Medum.ru. Archived from the original on 10 October 2022. Retrieved 15 May 2023.
  2. 1 2 "Arelpivir". Russian drug reference. Medum.ru. Archived from the original on 28 March 2023. Retrieved 15 May 2023.
  3. ↑ "Glenmark launches Covid-19 drug FabiFlu, priced at Rs 103 per tablet". Business Standard India. Press Trust of India. 20 June 2020. Archived from the original on 28 March 2023. Retrieved 15 May 2023.
  4. 1 2 Du YX, Chen XP (April 2020). "Favipiravir: pharmacokinetics and concerns about clinical trials for 2019-nCoV infection". Clinical Pharmacology and Therapeutics. 108 (2): 242–247. doi:10.1002/cpt.1844. PMID 32246834.
  5. ↑ Furuta, Yousuke; Takahashi, Kazumi; Shiraki, Kimiyasu; Sakamoto, Kenichi; Smee, Donald F.; Barnard, Dale L.; Gowen, Brian B.; Julander, Justin G.; Morrey, John D. (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.
  6. 1 2 3 4 5 6 Shiraki K, Daikoku T (February 2020). "Favipiravir, an anti-influenza drug against life-threatening RNA virus infections". Pharmacology & Therapeutics. 209: 107512. doi:10.1016/j.pharmthera.2020.107512. PMC 7102570. PMID 32097670.
  7. ↑ EJ Lane (22 June 2016). "Fujifilm in Avigan API license with Zhejiang Hisun Pharmaceuticals". Fierce Pharma. Archived from the original on 8 May 2020. Retrieved 20 April 2020.
  8. ↑ "Information of Avigan Tablet in relation to Covid-19 | FUJIFILM Toyama Chemical Co., Ltd". Archived from the original on 9 August 2022. Retrieved 15 May 2023.
  9. ↑ Pilkington, Victoria; Pepperrell, Toby; Hill, Andrew (2020). "A review of the safety of favipiravir – a potential treatment in the COVID-19 pandemic?". Journal of Virus Eradication. 6 (2): 45–51. doi:10.1016/S2055-6640(20)30016-9. ISSN 2055-6640. PMC 7331506. PMID 32405421.
  10. 1 2 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.
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  12. ↑ 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.
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  14. ↑ 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.
  15. ↑ "MediVector Completes Patient Enrollment In Two Phase 3 Studies Of Favipiravir For Influenza". BioSpace. Archived from the original on 4 November 2020. Retrieved 5 May 2020.
  16. ↑ Lumby, Casper (3 March 2020). "Favipiravir and Zanamivir Cleared Infection with Influenza B in a Severely Immunocompromised Child". Clinical Infectious Diseases. 71 (7): e191–e194. doi:10.1093/cid/ciaa023. PMID 32124919.
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  44. ↑ Dawes, Brian E.; Kalveram, Birte; Ikegami, Tetsuro; Juelich, Terry; Smith, Jennifer K.; Zhang, Lihong; Park, Arnold; Lee, Benhur; Komeno, Takashi; Furuta, Yousuke; Freiberg, Alexander N. (15 May 2018). "Favipiravir (T-705) protects against Nipah virus infection in the hamster model". Scientific Reports. 8 (1): 7604. Bibcode:2018NatSR...8.7604D. doi:10.1038/s41598-018-25780-3. ISSN 2045-2322. PMC 5954062. PMID 29765101.
  45. ↑ Furuta 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.
  46. ↑ 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.
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  49. ↑ 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.
  50. ↑ Murphy J, Sifri CD, Pruitt R, Hornberger M, Bonds D, Blanton J, et al. (January 2019). "Human Rabies - Virginia, 2017". MMWR. Morbidity and Mortality Weekly Report. 67 (5152): 1410–1414. doi:10.15585/mmwr.mm675152a2. PMC 6334827. PMID 30605446.
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