Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza

BACKGROUND: The pharmacokinetics and appropriate dose regimens of favipiravir are unknown in hospitalized influenza patients; such data are also needed to determine dosage selection for favipiravir trials in COVID-19.

METHODS: In this dose-escalating study, favipiravir pharmacokinetics and tolerability were assessed in critically ill influenza patients.

Participants received one of two dosing regimens; Japan licensed dose (1600 mg BID on day 1 and 600 mg BID on the following days) and the higher dose (1800 mg/800 mg BID) trialed in uncomplicated influenza.

The primary pharmacokinetic endpoint was the proportion of patients with a minimum observed plasma trough concentration (C(trough)) ≥20 mg/L at all measured time points after the second dose.

RESULTS: Sixteen patients were enrolled into the low dose group and 19 patients into the high dose group of the study.

Favipiravir C(trough) decreased significantly over time in both groups (p <0.01).

Relative to day 2 (48 hrs), concentrations were 91.7% and 90.3% lower in the 1600/600 mg group and 79.3% and 89.5% lower in the 1800/800 mg group at day 7 and 10, respectively.

In contrast, oseltamivir concentrations did not change significantly over time.

A 2-compartment disposition model with first-order absorption and elimination described the observed favipiravir concentration-time data well.

Modeling demonstrated that less than 50% of patients achieved C(trough) ≥20 mg/L for >80% of the duration of treatment of the two dose regimens evaluated (18.8% and 42.1% of patients for low and high dose regimen, respectively).

Increasing the favipravir dosage predicted a higher proportion of patients reaching this threshold of 20 mg/L, suggesting that dosing regimens of ≥3600/2600 mg might be required for adequate concentrations.

The two dosing regimens were well-tolerated in critical ill patients with influenza.

CONCLUSION: The two dosing regimens proposed for uncomplicated influenza did not achieve our pre-defined treatment threshold.