Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza
单位：[a]Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-JapanFriendship Hospital, Beijing, China[b]Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China[c]Department of Respiratory Medicine, Capital Medical University, Beijing, China[d]Beijing Institute of Pharmacology and Toxicology, Beijing, China[e]Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom[f]Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand[g]Department of Pulmonary and Critical Care Medicine, First Affliated Hospital of Soochow University, Jiangsu Province, China[h]Department of Pulmonary and Critical Care Medicine, Fujian Provincial Hospital, Fujian Province, China[i]The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China[j]Department of Research Laboratory, Toyama Chemical Co., Ltd., Tokyo, Japan[k]National Institute for Viral Disease Control and Prevention, Collaboration Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Centerfor Disease Control and Prevention, Key Laboratory for Medical Virology, National Health and Family Planning Commission, Beijing, China[l]Department of Respiratory, Emergency and Critical Care Medicine, First Affliated Hospital of Soochow University, Jiangsu Province, China[m]Surgical Intensive Care Unit, China-Japan Friendship Hospital, Beijing, China[n]Nosocomial Infection Control Office, China-Japan Friendship Hospital, Beijing, China[o]Suzhou HQ Bioscience Co., LTD, China[p]Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, United States
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. (C) 2020 The Authors. Published by Elsevier B.V.
基金：
Emergency Special Project of the Ministry of Science and Technology [10600100000015001206]; National Science and Technology Major Project [2017ZX10204401004, 2017ZX10103004]; CAMS Innovation Fund for Medical Sciences [CIFMS 2018-I2M-1-003]; Tsinghua University-Peking University Joint Center for Life Sciences; UK Public Health Rapid Support Team - United Kingdom Department of Health and Social Care; Wellcome TrustWellcome TrustEuropean Commission; Bill and Melinda Gates FoundationBill & Melinda Gates Foundation
第一作者单位：[a]Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-JapanFriendship Hospital, Beijing, China[b]Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China[c]Department of Respiratory Medicine, Capital Medical University, Beijing, China
共同第一作者：
通讯作者：
通讯机构：[a]Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-JapanFriendship Hospital, Beijing, China[b]Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China[c]Department of Respiratory Medicine, Capital Medical University, Beijing, China
推荐引用方式(GB/T 7714)：
Yeming Wang,Wu Zhong,Alex Salam,et al.Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza[J].EBIOMEDICINE.2020,62:doi:10.1016/j.ebiom.2020.103125.
APA：
Yeming Wang,Wu Zhong,Alex Salam,Joel Tarning,Qingyuan Zhan...&Bin Cao.(2020).Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza.EBIOMEDICINE,62,
MLA：
Yeming Wang,et al."Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza".EBIOMEDICINE 62.(2020)
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