tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Wu Zhong[SUP] 2 [/SUP], Alex Salam[SUP] 3 [/SUP], Joel Tarning[SUP] 4 [/SUP], Qingyuan Zhan[SUP] 1 [/SUP], Jian-An Huang[SUP] 5 [/SUP], Heng Weng[SUP] 6 [/SUP], Changqing Bai[SUP] 7 [/SUP], Yanhong Ren[SUP] 1 [/SUP], Koichi Yamada[SUP] 8 [/SUP], Dayan Wang[SUP] 9 [/SUP], Qiang Guo[SUP] 10 [/SUP], Qiongqiong Fang[SUP] 9 [/SUP], Sakurai Tsutomu[SUP] 8 [/SUP], Xiaohui Zou[SUP] 1 [/SUP], Haibo Li[SUP] 1 [/SUP], Annelies Gillesen[SUP] 3 [/SUP], Lyndsey Castle[SUP] 3 [/SUP], Cheng Chen[SUP] 5 [/SUP], Hongyan Li[SUP] 6 [/SUP], Jing Zhen[SUP] 7 [/SUP], Binghuai Lu[SUP] 1 [/SUP], Jun Duan[SUP] 11 [/SUP], Liping Guo[SUP] 12 [/SUP], Jinfang Jiang[SUP] 13 [/SUP], Ruiyuan Cao[SUP] 2 [/SUP], Guohui Fan[SUP] 1 [/SUP], Jintong Li[SUP] 14 [/SUP], Frederick G Hayden[SUP] 15 [/SUP], Chen Wang[SUP] 1 [/SUP], Peter Horby[SUP] 3 [/SUP], Bin Cao[SUP] 16 [/SUP]
Affiliations
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 (C[SUB]trough[/SUB]) ≥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[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.
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.
. 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[SUP] 1 [/SUP], Wu Zhong[SUP] 2 [/SUP], Alex Salam[SUP] 3 [/SUP], Joel Tarning[SUP] 4 [/SUP], Qingyuan Zhan[SUP] 1 [/SUP], Jian-An Huang[SUP] 5 [/SUP], Heng Weng[SUP] 6 [/SUP], Changqing Bai[SUP] 7 [/SUP], Yanhong Ren[SUP] 1 [/SUP], Koichi Yamada[SUP] 8 [/SUP], Dayan Wang[SUP] 9 [/SUP], Qiang Guo[SUP] 10 [/SUP], Qiongqiong Fang[SUP] 9 [/SUP], Sakurai Tsutomu[SUP] 8 [/SUP], Xiaohui Zou[SUP] 1 [/SUP], Haibo Li[SUP] 1 [/SUP], Annelies Gillesen[SUP] 3 [/SUP], Lyndsey Castle[SUP] 3 [/SUP], Cheng Chen[SUP] 5 [/SUP], Hongyan Li[SUP] 6 [/SUP], Jing Zhen[SUP] 7 [/SUP], Binghuai Lu[SUP] 1 [/SUP], Jun Duan[SUP] 11 [/SUP], Liping Guo[SUP] 12 [/SUP], Jinfang Jiang[SUP] 13 [/SUP], Ruiyuan Cao[SUP] 2 [/SUP], Guohui Fan[SUP] 1 [/SUP], Jintong Li[SUP] 14 [/SUP], Frederick G Hayden[SUP] 15 [/SUP], Chen Wang[SUP] 1 [/SUP], Peter Horby[SUP] 3 [/SUP], Bin Cao[SUP] 16 [/SUP]
Affiliations
- PMID: 33232871
- DOI: 10.1016/j.ebiom.2020.103125
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 (C[SUB]trough[/SUB]) ≥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[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.
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.