Oral Favipiravir Exposure and Pharmacodynamic Effects in Adult Outpatients With Acute Influenza

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 BID on day 1, 800 mg BID on days 2 to 5)(N = 827) or placebo (N = 419) in two phase 3 trials. Post hoc analyses assessed the frequency of reaching an average C-min >= 20ug/ml, its association with antiviral efficacy, and factors associated with reduced favipiravir exposure.Results: Wide inter-individual variability existed in favipiravir concentrations, and this regimen failed to reach an average C-min >20ug/ml in 41-43% of participants. Those attaining this threshold showed greater reductions in nasopharyngeal infectious virus titers on treatment days 2 and 3 (approximately 0.3-0.4 log10TCID50/ml) and lower viral titer AUCs compared to those who did not. Those with average C-min <20ug/ml had over 2-fold higher mean ratios of the metabolite T-705-M1 to favipiravir, consistent with greater metabolism, and were more likely to weigh >= 80 kg (61.5-64%).Conclusions: Higher favipiravir levels with average C-min >20ug/ml were associated with larger antiviral effects and more rapid illness alleviation compared to placebo and to favipiravir recipients with lower average C-min values in uncomplicated influenza.