Favipiravir

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

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

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

There is evidence that use during pregnancy may result in harm to the baby. Teratogenic and embryotoxic effects were shown on four animal species. In one case report, a 6-month old infant developed benign bright blue discolouration of the cornea after treatment with favipiravir which resolved after treatment cessation.

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

Favipiravir-RTP is a nucleoside analogue. It mimics both guanosine and adenosine nucleobases for viral RNA dependant RNA polymerase (RdRp). Incorporating two favipiravir ribofuranosyl bases in a row stops extension of the newly made RNA, although it is unclear how as of 2013.

There are multiple pathways to synthesize favipiravir. One synthesis starts with a pyrazine carboxylic acid, which is first reacted with thionyl chloride and then aqueous ammonia to produce 3-Hydroxypyrazine-2-carboxamide. The resulting material is nitrated with potassium nitrate and sulfuric acid to add a nitro group in the 6 position, which is then reduced using hydrazine hydrate to the corresponding amine. Finally, the amine is turned into a diazonium group using sodium nitrite and replaced with a fluorine group using hydrofluoric acid.

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. Favipiravir remains unapproved in the UK and the USA. In 2014, Japan approved favipiravir for treating influenza strains unresponsive to current antivirals. 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.