Favipiravir, an influenza virus RNA polymerase inhibitor, and peramivir, an 
influenza virus neuraminidase inhibitor, were evaluated alone and in combination 
against pandemic influenza A/California/04/2009 (H1N1) virus infections in mice. 
Infected mice were treated twice daily for 5 d starting 4 h after virus 
challenge. Favipiravir was 40%, 70%, and 100% protective at 20, 40, and 100 
mg/kg/d. Peramivir was 30% protective at 0.5 mg/kg/d, but ineffective at lower 
doses when used as monotherapy. Combinations of favipiravir and peramivir 
increased the numbers of survivors by 10-50% when the 0.025, 0.05, and 0.1 
mg/kg/d doses of peramivir were combined with 20 mg/kg/d favipiravir and when 
all doses of peramivir were combined with 40 mg/kg/d favipiravir. 
Three-dimensional analysis of drug interactions using the MacSynergy method 
indicates strong synergy for these drug combinations. In addition, an increase 
in lifespan for groups of mice treated with drug combinations, compared to the 
most effective monotherapy group, was observed for the 0.025, 0.05, and 0.1 
mg/kg/d doses of peramivir combined with favipiravir at the 20 mg dose level. 
Therefore, the 20 mg/kg/d dose of favipiravir was selected for further 
combination studies. Increased survival was exhibited when this dose was 
combined with peramivir doses of 0.1, 0.25 and 0.5 mg/kg/d (1 mg/kg/d of 
peramivir alone was 100% protective in this experiment). Improved body weight 
relative to either compound alone was evident using 0.25, 0.5, and 1 mg/kg/d of 
peramivir. Significant reductions in lung hemorrhage score and lung weight were 
evident on day 6 post-infection. In addition, virus titers were reduced 
significantly on day 4 post-infection by combination therapy containing 
favipiravir combined with peramivir at 0.25 and 0.5 mg/kg/d. These data 
demonstrate that combinations of favipiravir and peramivir perform better than 
suboptimal doses of each compound alone for the treatment of influenza virus 
infections in mice.