Clinical Pharmacokinetics and Safety of Remdesivir in Phase I Participants with Varying Degrees of Renal Impairment.

IF 4.6 2区医学 Q1 PHARMACOLOGY & PHARMACY Clinical Pharmacokinetics Pub Date : 2024-11-19 DOI:10.1007/s40262-024-01453-5

Haeyoung Zhang, Rita Humeniuk, Sean Regan, Yiannis Koullias, Santosh Davies, Amy John, Gong Shen, Deqing Xiao, Robert H Hyland, Helen Winter, Aryun Kim

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Abstract

Background and objective: Remdesivir is a nucleotide analog prodrug approved for the treatment of COVID-19. This study evaluated the pharmacokinetics and safety of remdesivir and its metabolites (GS-704277 and GS-441524) in participants with varying degrees of renal impairment. Results of this phase I study, along with those of a phase III study, contributed to an extension of indication for remdesivir in the USA and Europe for use in patients with COVID-19 with all stages of renal impairment, including those on dialysis, with no dose adjustment.

Methods: This phase I, open-label, parallel-group study enrolled participants who had mild (n = 12), moderate (n = 11), or severe (n = 10) renal impairment or kidney failure (n = 6 with dialysis, n = 4 without dialysis). Healthy matched controls were enrolled as reference. Remdesivir was given as single intravenous doses of 100 mg (mild and moderate renal impairment), 40 mg (severe renal impairment, kidney failure predialysis), and 20 mg (kidney failure postdialysis and without dialysis).

Results: Plasma pharmacokinetics of remdesivir were not affected by mild, moderate, or severe renal impairment or kidney failure. Geometric least squares mean ratios ranged from 0.8 to 1.2 for remdesivir area under the plasma concentration-time curve (AUC). GS-704277 AUC was up to 2.8-fold higher and GS-441524 AUC up to 7.9-fold higher in participants with renal impairment. Adverse events and laboratory abnormalities were consistent with the existing safety profile for remdesivir.

Conclusions: Observed pharmacokinetics for remdesivir and its metabolites in participants with renal impairment aligned with expected changes based on known routes of elimination. Remdesivir was generally safe and well tolerated in participants with renal impairment, and no new safety concerns were identified. These results, along with those from the phase III study in patients with COVID-19 with severely reduced kidney function, support the use of remdesivir in patients with any degree of renal impairment with no dose adjustments.

Trial registration: EudraCT no. 2020-003441-10; 9 July 2020.

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雷米替韦在不同程度肾功能受损的 I 期参与者中的临床药代动力学和安全性。

背景和目的：雷米替韦是一种核苷酸类似物原药，已被批准用于治疗COVID-19。该研究评估了雷米替韦及其代谢物（GS-704277 和 GS-441524）在不同程度肾功能受损的参与者中的药代动力学和安全性。这项I期研究的结果以及一项III期研究的结果有助于扩大雷米替韦在美国和欧洲的适应症，使其适用于各期肾功能受损的COVID-19患者，包括透析患者，且无需调整剂量：这项 I 期、开放标签、平行分组研究招募了轻度（12 人）、中度（11 人）或重度（10 人）肾功能损害或肾衰竭患者（6 人有透析，4 人无透析）。健康匹配对照组作为参照。雷米地韦的单次静脉注射剂量为100毫克（轻度和中度肾功能损害）、40毫克（重度肾功能损害、透析前肾衰竭）和20毫克（透析后肾衰竭和未透析）：结果：雷米地韦的血浆药代动力学不受轻度、中度、重度肾功能损害或肾衰竭的影响。雷米替韦血浆浓度-时间曲线下面积（AUC）的几何最小二乘法平均比率为 0.8 至 1.2。肾功能受损者的 GS-704277 AUC 高出 2.8 倍，GS-441524 AUC 高出 7.9 倍。不良事件和实验室异常与雷米替韦现有的安全性概况一致：肾功能受损者体内观察到的雷米替韦及其代谢物的药代动力学与基于已知消除途径的预期变化一致。肾功能受损者对雷米替韦的安全性和耐受性总体良好，没有发现新的安全性问题。这些结果以及在肾功能严重受损的COVID-19患者中进行的III期研究结果支持在任何程度的肾功能受损患者中使用雷米替韦，且无需调整剂量：试验注册：EudraCT 编号：2020-003441-10；2020 年 7 月 9 日。

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来源期刊

Clinical Pharmacokinetics 医学-药学

CiteScore

8.80

自引率

4.40%

发文量

审稿时长

6-12 weeks

期刊介绍： Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.