珐匹拉韦（T-705）联合奥司他韦治疗重症流感患者的 2a 期、开放标签、剂量递增、多中心药代动力学研究。

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

机构信息

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.

Beijing Institute of Pharmacology and Toxicology, Beijing, China.

出版信息

EBioMedicine. 2020 Dec;62:103125. doi: 10.1016/j.ebiom.2020.103125. Epub 2020 Nov 22.

DOI:10.1016/j.ebiom.2020.103125

PMID:33232871

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7689521/

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) ≥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 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 ≥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.

摘要

背景

住院流感患者的法维拉韦药代动力学和适当剂量方案尚不清楚；为了确定法维拉韦在 COVID-19 中的试验剂量选择，也需要这些数据。

方法

在这项剂量递增研究中，评估了危重症流感患者中法维拉韦的药代动力学和耐受性。参与者接受了两种剂量方案中的一种；日本许可剂量（第 1 天 1600mg 每日两次，随后几天 600mg 每日两次）和在单纯性流感中试验的较高剂量（1800mg/800mg 每日两次）。主要药代动力学终点是所有测量时间点第二次给药后最小观察到的血浆谷浓度（C）≥20mg/L 的患者比例。

结果

16 名患者被纳入低剂量组，19 名患者被纳入高剂量组。两组患者的法维拉韦 C 均随时间显著下降（p<0.01）。与第 2 天（48 小时）相比，第 7 天和第 10 天，1600/600mg 组分别为 91.7%和 90.3%，1800/800mg 组分别为 79.3%和 89.5%。相比之下，奥司他韦浓度随时间变化不明显。一个两室分布模型，具有一级吸收和消除，很好地描述了观察到的法维拉韦浓度-时间数据。模型表明，两种剂量方案评估的治疗持续时间超过 80%的时间，只有不到 50%的患者达到 C≥20mg/L（低剂量方案和高剂量方案的患者分别为 50%和 42.1%）。增加法维拉韦剂量预测达到 20mg/L 这一阈值的患者比例更高，表明需要≥3600/2600mg 的剂量方案才能达到足够的浓度。两种剂量方案在重症流感患者中耐受良好。