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

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


    EBioMedicine


    . 2020 Nov 21;62:103125.
    doi: 10.1016/j.ebiom.2020.103125. Online ahead of print.
    Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza


    Yeming Wang 1 , Wu Zhong 2 , Alex Salam 3 , Joel Tarning 4 , Qingyuan Zhan 1 , Jian-An Huang 5 , Heng Weng 6 , Changqing Bai 7 , Yanhong Ren 1 , Koichi Yamada 8 , Dayan Wang 9 , Qiang Guo 10 , Qiongqiong Fang 9 , Sakurai Tsutomu 8 , Xiaohui Zou 1 , Haibo Li 1 , Annelies Gillesen 3 , Lyndsey Castle 3 , Cheng Chen 5 , Hongyan Li 6 , Jing Zhen 7 , Binghuai Lu 1 , Jun Duan 11 , Liping Guo 12 , Jinfang Jiang 13 , Ruiyuan Cao 2 , Guohui Fan 1 , Jintong Li 14 , Frederick G Hayden 15 , Chen Wang 1 , Peter Horby 3 , Bin Cao 16



    AffiliationsFree article

    Abstract

    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 (Ctrough) ≥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 Ctrough 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 Ctrough ≥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.

    Keywords: COVID-19; Concentration; Critical illness; Favipiravir; Influenza; Intensive care; Pharmacokinetics.

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