2.6. Favipiravir (Avigan, T-705)
Favipiravir was originally developed by Fujifilm group, Japan. It is a pyrazine-carboxamide derivative (Figure 4) with a broad-spectrum antiviral activity. It selectively and potently inhibits the RdRp of RNA viruses [69]. Favipiravir is a prodrug that requires bioactivation in host-infected cells. Its active form is favipiravir-ribose-5′-triphosphate. The first step in the formation of the active species is potentially catalyzed by human hypoxanthine guanine phosphoribosyl-transferase [70], which converts favipiravir into ribose-5′-monophosphate intermediate. The latter intermediate undergoes two phosphorylation steps mediated by the action of host kinases leading to the formation of the ribose-5′-triphosphate active form.
Favipiravir is effective against several strains of influenza viruses, including those that are resistant to existing anti-influenza drugs. Favipiravir also showed an antiviral activity in experimental animals against other RNA viruses, including arenaviruses, alphaviruses, bunyaviruses, and flaviviruses [71]. Furthermore, preliminary results also indicated that favipiravir potentially possesses a moderate activity against Ebola [72]. Importantly, a recent nonrandomized, open-label study in patients (n = 80) with non-severe COVID-19 showed that favipiravir (1600 mg orally twice daily on the first day, then 600 mg orally twice daily for thirteen days) with INF-α had significantly better therapeutic effects on SARS-CoV-2 infection, in terms of disease progression and viral clearance, than lopinavir/ritonavir with INF-α [73]. Furthermore, an open-label, prospective, randomized, multicenter study in adults (n = 236) with COVID-19 pneumonia in China revealed that favipiravir (1600 mg orally twice daily on the first day, then 600 mg orally twice daily for 7–10 days) was associated with a higher 7-day clinical recovery rate compared to a control group treated with umifenovir, a potential inhibitor of the membrane fusion stage during the virus infection, (200 mg three times daily for 7–10 days). The 7-day clinical recovery rate in patients with moderate COVID-19 pneumonia was 71% in the favipiravir-treated patients, whereas the rate was 56% in the umifenovir-treated patients. Likewise, the 7-day clinical recovery rate in patients with severe to critical COVID-19 pneumonia was 6% versus 0%, respectively [74]. Currently, favipiravir is being studied alone or in combination with tocilizumab, hydroxychloroquine, or oseltamivir for the treatment of COVID-19 in more than 23 clinical trials across the world.
As of now, favipiravir is not available in the U.S. or European countries, perhaps because the animal experiments showed that the antiviral agent can be associated with teratogenic effects. Favipiravir is contraindicated in women with known or suspected pregnancy [75]. Favipiravir is also associated with QT prolongation [76]. It is currently approved to treat novel or re-emerging influenza outbreaks in China and Japan, and it is available as an oral solid dosage form [73,74,76].