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<h4>Background</h4>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.<h4>Methods</h4>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<sub>trough</sub>) ≥20 mg/L at all measured time points after the second dose.<h4>Results</h4>Sixteen patients were enrolled into the low dose group and 19 patients into the high dose group of the study. Favipiravir C<sub>trough</sub> 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<sub>trough</sub> ≥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.<h4>Conclusion</h4>The two dosing regimens proposed for uncomplicated influenza did not achieve our pre-defined treatment threshold.

Original publication

DOI

10.1016/j.ebiom.2020.103125

Type

Journal

EBioMedicine

Publication Date

12/2020

Volume

62

Addresses

Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Department of Respiratory Medicine, Capital Medical University, Beijing, China.

Keywords

Humans, Amides, Pyrazines, Drug Therapy, Combination, Severity of Illness Index, Aged, Middle Aged, Female, Male, Influenza, Human, Oseltamivir