Favipiravir (T-705) is a nucleoside analog that was recently approved as an anti-influenza drug in Japan, and is in Phase 3 clinical trials in the USA for the same indication. It is active against a growing list of virulent RNA viruses including Ebola virus, and the author studies show that it is highly protective in rodent models of Argentine hemorrhagic fever (AHF), caused by Junin virus (JUNV). Favipiravir appears to act by directly inhibiting the viral RNA-dependent RNA polymerase (RdRP), with minimal effect on cellular nucleoside metabolism or intracellular nucleic acid pools. There is little evidence that resistant viruses are selected during the course of therapy, indicating that the drug’s target site is essential for efficient virus replication.
At present, the nucleoside analog ribavirin is the only FDA-approved drug with broad-spectrum activity against RNA viruses. However, even though many studies since the early 1980s show that ribavirin blocks the replication of many different viral agents in vitro, and that it is protective in numerous animal models of RNA viral infection, it is in regular clinical use only in combination with interferon for the therapy of chronic hepatitis C. Although smallscale trials have found ribavirin beneficial for the treatment of two arenaviral infections, Lassa fever and AHF, it can only be used off-label for those indications. The restricted clinical use of a drug with known broad-spectrumantiviral activity in vitro and in animal models reflects both ribavirin’s somewhat limited efficacy and its side-effect of hemolytic anemia, caused by a dose-related reduction in intracellular guanosine triphosphate (GTP) levels.
- Addition of low-dose ribavirin enhances favipiravir protection of PICV-infected hamsters
In the initial combination therapy study in PICV-infected hamsters with treatment beginning on day 6 p.i., the author found that 200mg/kg/day of favipiravir plus 35 mg/kg/day of ribavirin resulted in 80% survival, as compared to 20% survival in placebo-treated controls. However, the same dose of ribavirin alone also produced 80% protection, so no beneficial effect of combined therapy was evident. Similarly, a regimen of 100 mg/kg/day of favipiravir combined with 35 mg/kg/day of ribavirin did not improve upon ribavirin alone. At a level of ribavirin that gave less protection, it was possible to detect a benefit of combined therapy. When ribavirin was decreased to 17.5 mg/kg/day, only 20% of infected hamsters survived, and decreasing favipiravir from 200 to 100 mg/kg/day also reduced the level of protection.When the low-dose of 17.5mg/kg/day ribavirinwas added to either dose of favipiravir, there was a significant increase in survival. Further analysis using the MacSynergy II program indicated favorable interactions between favipiravir and low-dose ribavirin, with a volume of synergy of 53.1, consistent with a moderate synergistic effect.
- Addition of low-dose ribavirin enhances favipiravir protection of JUNV-infected guinea pigs
In the experiment, the author reduced the dose of both drugs, giving 250 mg/kg/day of favipiravir and 25 mg/kg/day of ribavirin. As before, placebo-treated animals developed fever and weight loss beginning 5-6 days after virus challenge. All animals that received either drug alone succumbed to infection, though their deaths were delayed by 6-7 days compared to the placebo group. In contrast, five of six guinea pigs that received the combination therapy survived, a significant (P < 0.01) improvement over either drug alone. Animals in the combined treatment group stopped gaining weight on approximately day 7 p.i., then began to recover before the end of the treatment period. In contrast, those that only received ribavirin progressively lost weight, beginning on approximately day 11 p.i., while animals treated with favipiravir alone continued to gain weight through approximately day 13-14, then rapidly lost weight. Interestingly, increased body temperatures were measured on days 6-12 in placebo-treated animals and on days 13-18 in those that received only favipiravir, but fever was not detected in animals that received both drugs or ribavirin alone.
The doses of favipiravir and ribavirin administered to rodents in the present study appear to reasonably reflect tolerated doses in humans. For favipiravir, a dose of 250 mg/kg in a rodent is equivalent to approximately 54 mg/kg, based on a 60 kg person. In the recent Ebola clinical trial, patients received 100 mg/kg for day 1, with a 40 mg/kg maintenance dose administered on days 2-10. Similarly, a rodent dose of 25 mg/kg of ribavirin is approximately equivalent to 5.5 mg/kg in humans, far below the amount given to patients with AHF in a small clinical trial (85 mg/kg on day 1, 68 mg/kg on days 2e5, and 24 mg/kg for the last 6 days of treatment). Because favipiravir is well tolerated at a dose of 500mg/kg/day, the best strategy for future animal studies may be to increase the dose of favipiravir and further reduce the amount of ribavirin.
Reference：
Jonna B. Westover, Antiviral Research 126 (2016) 62-68