Abstract
BACKGROUND: The pharmacokinetics of oral favipiravir and the relationships of plasma concentrations to antiviral effects are incompletely studied in influenza. METHODS: Serial plasma samples were collected from adults with uncomplicated influenza who were randomized to favipiravir (1800 mg twice a day on day 1, 800 mg twice a day on days 2 to 5; n = 827) or placebo (n = 419) in 2 phase 3 trials. Post hoc analyses assessed the frequency of reaching an average minimum concentration (Cmin) ≥20 µg/mL, its association with antiviral efficacy, and factors associated with reduced favipiravir exposure. RESULTS: Wide interindividual variability existed in favipiravir concentrations, and this regimen failed to reach an average Cmin>20 µg/mL in 41%-43% of participants. Those attaining this threshold showed greater reductions in nasopharyngeal infectious virus titers on treatment days 2 and 3 and lower viral titer area under the curve compared to those who did not. Those with average Cmin <20 µg/mL had over 2-fold higher mean ratios of the metabolite T-705M1 to favipiravir, consistent with greater metabolism, and were more likely to weigh >80 kg (61.5%-64%). CONCLUSIONS: Higher favipiravir levels with average Cmin>20 µg/mL were associated with larger antiviral effects and more rapid illness alleviation compared to placebo and to favipiravir recipients with lower average Cmin values in uncomplicated influenza. Clinical Trials Registration . NCT1068912 and NCT01728753.