Favipiravir

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.[4] 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,[1] Areplivir,[2] others
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.[5] In 2016, Fujifilm licensed it to Zhejiang Hisun Pharmaceutical Co. of China.[6] It became a generic drug in 2019, allowing the company to produce it in the People's Republic of China. In 2019, the patent of the compound of this agent expired, and it became a generic drug that other manufacturers could produce.

Medical use

Favipiravir has been approved to treat influenza in Japan.[5] It is, however, only indicated for novel influenza (strains that cause more severe disease) rather than seasonal influenza.[5] As of 2020, the probability of resistance developing appears low.[5]

Side effects

There is evidence that use during pregnancy may result in harm to the baby.[5]

Mechanism of action

The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase.[7] Other research suggests that favipiravir induces lethal RNA transversion mutations, producing a nonviable viral phenotype.[8] Favipiravir is a prodrug that is metabolized to its active form, favipiravir-ribofuranosyl-5'-triphosphate (favipiravir-RTP), available in both oral and intravenous formulations.[9][10] Human hypoxanthine guanine phosphoribosyltransferase (HGPRT) is believed to play a key role in this activation process.[11] Favipiravir does not inhibit RNA or DNA synthesis in mammalian cells and is not toxic to them.[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]

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.[15] 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.[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]

On 15 March 2020, the drug was approved in China for the treatment of COVID-19.[19] 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.[20][21]

Society and culture

Brand names

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

Research

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

In February 2020, favipiravir was being studied in China for experimental treatment of the emergent COVID-19.[24][25] Trials are also being planned in Japan.[26]

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.[27][28]

The drug has been approved for use in clinical trials of coronavirus disease 2019 in China.[19] Due to COVID-19, favipiravir was approved for sale rapidly in February 2020 in China. Data from clinical trials of favipiravir against COVID-19 was published by the Ministry of Science and Technology of the People's Republic of China at a COVID-19 themed press conference on March 17, according to which, favipiravir has shown good clinical efficacy against the disease. And its tablet form also makes it easily accessible, which helps reduce the burden on medical resources by enabling non-critically ill patients to take the medicine at home. Once favipiravir was launched in the Chinese market, it was listed as one of the Major Anti-pandemic Materials by China's State Council, and the Chinese government has unified the allocation of favipiravir supplies. Since the outbreak of COVID-19, in addition to satisfying the domestic treatment and strategic reserve demand, the medication has also been used to support over 30 countries in battling COVID-19 and achieved good results. All Favipiravir tablets in China are manufactured by Zhejiang Hisun Pharmaceutical Co., Ltd., who recently has been honored by the Chinese State Council as the “Ordnance Factory” responding to the COVID-19 crisis. 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.[29] The Italian Pharmaceutical Agency, however, has reminded the public that the existing evidence in support of this drug is scant and preliminary.[30] There are plans to study it in three hospitals in Massachusetts, USA as of April 20, 2020.[31] As of early May 2020, a trial is starting in London, UK.[32]

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.[33] 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.[34] On May 30, 2020, the Russian Health Ministry approved a generic version of favipiravir named Avifavir. Russian Direct Investment Fund (RDIF) backed the development of Avifavir and found it highly effective in the first phase of clinical trials.[35][36][37] On June 25, 2020, the Russian Ministry of Health approved one more drug based on favipiravir. A trial of 50 patients in Bangladesh lead to a 96% recovery rate of severe cases after 10 days versus 52% for control.[38]

Ebola

Research in 2014 suggested that favipiravir may have efficacy against Ebola based on studies in mouse models; efficacy in humans was unaddressed.[39][40][41]

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.[42] A clinical trial investigating the use of favipiravir against Ebola virus disease began in Guéckédou, Guinea, in December 2014.[43] 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][44][45] The trial design was concomitantly criticised for using only historical controls.[46]

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.[47] 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.[48]

Favipiravir is currently undergoing global multicenter clinical trials in treating COVID-19. The clinical data published shows that favipiravir can clear the virus fast and alleviate the pneumonia symptom of COVID-19 patients with high tolerance and few adverse reactions. Notably, in all related studies, the dosage of favipiravir is higher and the duration of medication administration is longer than those recommended in the instructions. Dosage for the first day is 3,200-3,600 mg and 1,200-1,600 mg for the following days, lasting for 7–14 days.

According to the favipiravir versus Kaletra trial findings of The Third People's Hospital of Shenzhen, patients taking favipiravir recover faster than those taking Lopinavir/Ritonavir. And it took a shorter median time for the former (averaging 4 days, ranging from 2.5 to 9 days) than the latter (averaging 11 days, ranging from 8 to 13 days) to turn negative in tests, with a significant difference (P<0.001). The favipiravir group also showed significant improvement in chest imaging, with an improvement rate of 91.43% (32/35) versus 62.22% (28/45) of the control group (P = 0.004). The favipiravir treatment is an independent influencing factor for imaging improvement and virus clearing. In the meantime, patients in the favipiravir group have high tolerance and few adverse reactions.

Zhongnan Hospital of Wuhan University conducted a 240-patient multicenter, randomized, open, positive, parallel-controlled clinical study on the efficacy of favipiravir for novel coronavirus-infected pneumonia. The clinical test using Arbidol as control group found that the drug's efficacy on treating patients in the favipiravir group was markedly better than that of the drug taken by those in the control group. For ordinary patients with COVID-19, 7 day's clinical recovery rate was 55.86% in the Arbidol group and 71.43% in the favipiravir group (P=0.0199). The time for patients in the favipiravir group to recover from fever was notably shorter than that of the participants in the control group, with favipiravir-treated subjects recovering from fever within 2.5 days on average versus 4.2 days for other patients. Patients who took favipiravir were able to soothe their cough within an average of 4.57 days, compared with 5.98 days for those that did not take the drug. There were statistical differences between the two groups with regard to the above evaluation indexes. Analysis showed the rate of new dyspnea during the course of treatment in the Arbidol group was 11.67% (14/120) and that in the favipiravir group was 3.45% (4/116) (P=0.0174). For ordinary patients with COVID-19, the auxiliary oxygen therapy or noninvasive mechanical ventilation rate was 8.16% (8/98) in the favipiravir group and 17.12% (19/111) in the Arbidol group (P = 0.0541; 95% CI: -0.1781, -0.0009). For COVID-19 patients with hypertension and/or diabetes, the time of fever reduction and cough relief in the favipiravir group was also significantly shorter than that in the Arbidol group (P<0.0001). All these results indicate that favipiravir may effectively prevent progression to acute respiratory distress syndrome, shock and multiple organ failure in patients with moderate COVID-19 symptoms. Favipiravir is considered the first choice to treat ordinary COVID-19 patients who have never received antiviral therapy before, because it has higher 7 day's clinical recovery rate and can reduce incidence of fever and cough more effectively.

Another preliminary report of research carried out at Fujita Medical University, Japan on a sample of 2,158 patients with COVID-19 showed that almost all favipiravir-treated patients’ symptoms were improved: 70% of the patients with mild to moderate symptoms and 40% of those with severe symptoms recovered after a 7-day antiviral treatment, and 60% of the patients with severe symptoms recovered after a 14-day antiviral treatment.

Favipiravir has also produced encouraging results in an early clinical trial in Russia. Early data from the study showed that 60 percent of the 40 patients from six medical centers took favipiravir tablets and tested negative for the virus after five days. It was noticed that patients in the favipiravir group showed a faster improvement in the general health and clinical condition, which may lead to earlier discharge from hospital and reduce the burden on medical facilities by 30-40% in the near future. Thanks to the administration of favipiravir, most patients are not infectious as early as the fifth day of treatment, which is critical to containing the pandemic and ensuring a swift return to normal life.

The first stage of the trials has already been completed. It lasted 10 days and involved 60 patients with coronavirus infection with moderate illness. Forty people received favipiravir treatment and the other 20 patients from the control group underwent standard therapy. Favipiravir demonstrated safety with no new or previously unreported side effects detected. The drug's efficacy was above a threshold of 80%, which is the criterion for an antiviral drug with high antiviral activity. The body temperature of 68% of the patients taking favipiravir returned to normal earlier (on the third day) than in the control group (on the sixth day). On average, the complete elimination of the virus from the body as a result of favipiravir treatment occurred on the fourth day, while in the standard therapy group this process took nine days. Following the first four days of treatment, 65% of the 40 patients who took favipiravir tested negative for coronavirus, which is twice as many as in the standard therapy group. By day 10, the number of patients whose tests returned negative results reached 35 out of 40.

On May 21, the Ministry of Health of the Russian Federation approved the launch of the final stage, which will involve 330 patients compared with 60 during the initial stage. In total, 30 medical centers in nine Russian regions will conduct studies at the final stage. The clinical trial was expected to be completed by the end of May.

On May 31, the ministry published a new national drug catalogue which shows that favipiravir has become the first drug approved by the ministry to treat COVID-19.

On June 20, Glenmark Pharmaceuticals Ltd announced that it had received Indian regulatory approval, which was part of India's accelerated approval process, to make and sell oral antiviral drug favipiravir for treating mild-to-moderate COVID-19 infections in the country. Favipiravir also became the first drug approved in India for the treatment of COVID-19.

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.[12] Activity against enteroviruses[49] and Rift Valley fever virus has also been demonstrated.[50] Favipiravir has showed limited efficacy against Zika virus in animal studies, but was less effective than other antivirals such as MK-608.[51] The agent has also shown some efficacy against rabies,[52] and has been used experimentally in some humans infected with the virus.[53]

Tautomerism

The possible tautomerism of favipiravir 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. Upon protonation the keto form is switched on. However these findings were caveated with the need to confirm this experimentally.[54]

  • Enol-like tautomeric form
  • Keto-like tautomeric form
gollark: It's not THAT bad. I documented most of how it works and it's not even directly installed from pastebin now.
gollark: It makes more sense, yes, thus I will not implement it.
gollark: Except it's addition.
gollark: <@563866872702042132> I already did the calling-is-multiplication thing.
gollark: This occurs in the final phase of potatoBIOS initialization:```luaif potatOS.registry.get "potatOS.immutable_global_scope" then setmetatable(_G, { __newindex = function(_, x) error(("cannot set _G[%q] - _G is immutable"):format(tostring(x)), 0) end })endif meta then _G.meta = meta.new() endif _G.textutilsprompt then textutils.prompt = _G.textutilsprompt endif process then process.spawn(keyboard_shortcuts, "kbsd") if http.websocket then process.spawn(skynet.listen, "skynetd") process.spawn(potatoNET, "systemd-potatod") end local autorun = potatOS.registry.get "potatOS.autorun" if type(autorun) == "string" then autorun = load(autorun) end if type(autorun) == "function" then process.spawn(autorun, "autorun") end if potatOS.registry.get "potatOS.extended_monitoring" then process.spawn(excessive_monitoring, "extended_monitoring") end if run then process.spawn(run_shell, "ushell") endelse if run then print "Warning: no process manager available. This should probably not happen - please consider reinstalling or updating. Fallback mode enabled." local ok, err = pcall(run_shell) if err then printError(err) end os.shutdown() endendwhile true do coroutine.yield() end```

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