Favipiravir

Favipiravir, sold under the brand names Avigan, Abigan and FabiFlu[1], is an antiviral medication used to treat influenza in Japan.[2] It is also being studied to treat a number of other viral infections.[2] Like the experimental antiviral drugs (T-1105 and T-1106), it is a pyrazinecarboxamide derivative.

Favipiravir
Clinical data
Trade namesAvigan (アビガン, Abigan, Avifavir, Areplivir), FabiFlu
Other namesT-705, favipira, favilavir
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC5H4FN3O2
Molar mass157.104 g·mol−1
3D model (JSmol)

It is being developed and manufactured by Toyama Chemical (Fujifilm group) and was approved for medical use in Japan in 2014.[3] In 2016, Fujifilm licensed API for it to Zhejiang Hisun Pharmaceutical Co. of China.[4] It became a generic drug in 2019.

Medical use

Favipiravir has been approved to treat influenza in Japan.[3] It is, however, only indicated for novel influenza (strains that cause more severe disease) rather than seasonal influenza.[3] As of 2020, the probability of resistance developing appears low.[3]

Side effects

There is evidence that use during pregnancy may result in harm to the baby.[3]

Mechanism of action

The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase.[5] Other research suggests that favipiravir induces lethal RNA transversion mutations, producing a nonviable viral phenotype.[6] Favipiravir is a prodrug that is metabolized to its active form, favipiravir-ribofuranosyl-5'-triphosphate (favipiravir-RTP), available in both oral and intravenous formulations.[7][8] Human hypoxanthine guanine phosphoribosyltransferase (HGPRT) is believed to play a key role in this activation process.[9] Favipiravir does not inhibit RNA or DNA synthesis in mammalian cells and is not toxic to them.[10] In 2014, favipiravir was approved in Japan for stockpiling against influenza pandemics.[11] However, favipiravir has not been shown to be effective in primary human airway cells, casting doubt on its efficacy in influenza treatment.[12]

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.[13] 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.[14] In 2014, Japan approved favipiravir for treating influenza strains unresponsive to current antivirals.[15] 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.[16]

On 15 March 2020, the drug was approved in China for the treatment of Covid-19.[17] On 20 June 2020, the drug was approved in India for the treatment of Covid-19 patients under the brand name of Fabiflu manufactured by Glenmark. In India the drug is priced at Rs 103 per tablet.[18][19]

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.[20][21] Trials are also being planned in Japan.[22]

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.[23][24]

The drug has been approved for use in clinical trials of coronavirus disease 2019 in China.[17] 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.[25] The Italian Pharmaceutical Agency, however, has reminded the public that the existing evidence in support of this drug is scant and preliminary.[26] There are plans to study it in three hospitals in Massachusetts, USA as of April 20, 2020.[27] As of early May 2020, a trial is starting in London, UK.[28]

The drug was approved for the treatment of COVID-19 in the hospital settings in Russia on May 29, 2020, after an ongoing open-label randomized clinical trial had recruited 60 subjects on favipiravir.[29] According to the government clinical trial registry, this study COVID-FPR-01 is expected to recruit 390 subjects overall and finish by December 31, 2020.[30] On May 30, 2020, the Russian Health Ministry approved a generic version of favipiravir named Avifavir. RDIF backed the development of Avifavir and found it highly effective in the first phase of clinical trials.[31][32][33] On June 25, 2020, the Russian Ministry of Health approved one more drug based on favipiravir — Areplivir.

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 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).[1][39][40] The trial design was concomitantly criticised for using only historical controls.[41]

Nipah

Nipah virus, an enveloped RNA virus, associated with fever associated with encephalitis and acute respiratory distress out-breaks with high mortality. 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.[42] 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 perioral (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.[43]

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.[10] Activity against enteroviruses[44] and Rift Valley fever virus has also been demonstrated.[45] Favipiravir has showed limited efficacy against Zika virus in animal studies, but was less effective than other antivirals such as MK-608.[46] The agent has also shown some efficacy against rabies,[47] and has been used experimentally in some humans infected with the virus.[48]

References
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