Population Pharmacokinetic Modelling of Remdesivir and Its Metabolite GS-441524 in Hospitalised Patients with COVID-19.

IF 4.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Clinical Pharmacokinetics Pub Date : 2025-05-01 Epub Date: 2025-04-22 DOI:10.1007/s40262-025-01496-2

Darren M Roberts, Xin Liu, Suzanne L Parker, Andrew Burke, Jenny Peek, Jane E Carland, Bridin Murnion, Vincent Seah, Steven C Wallis, Chandra D Sumi, Saurabh Pandey, Hergen Buscher, Anthony Byrne, Indy Sandaradura, David Bowen, Simon Holz, Adam G Stewart, Krispin M Hajkowicz, Jason A Roberts

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引用次数: 0

Abstract

Background and objectives: There are limited data testing whether the licensed dose of remdesivir and its active metabolite GS-441524 achieve target concentrations in hospitalised patients with confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of coronavirus disease-2019 (COVID-19). The objectives of this study were to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalised patients treated for COVID-19 and develop a model to inform dose optimisation in clinical use.

Methods: This was a prospective, open-labelled, multi-centre, observational study in four Australian hospitals in adults with confirmed SARS-CoV-2 infection. Patients were administered the licensed remdesivir dose. Remdesivir and GS-441524 concentrations were quantified in multiple plasma samples at different times in the dosing interval by ultra-high-performance liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Patients were divided into two groups: pharmacokinetic model building and external validation. A population pharmacokinetic analysis was built using non-linear mixed-effects modelling. Monte Carlo simulations were performed to describe the impact of age, kidney function and dosing regimen on drug concentrations.

Results: In total, 33 patients were enrolled (median age 70 years, estimated glomerular filtration rate (eGFR) 80 mL/min/1.73 m²). The pharmacokinetics for both compounds were adequately described by a two-compartment model (one compartment for each compound) with first-order elimination. Key covariates included in the final model were age and eGFR. GS-441524 plasma concentrations exceeded the lowest reported half-maximal effective concentration (EC₅₀) with the recommended dosage, and higher dosages exceeded the lowest reported 90%-effective concentration (EC₉₀).

Conclusions: The licensed remdesivir dose may achieve target concentrations of GS-441524, but higher dosages may optimise outcomes. Dose adjustments are guided primarily by kidney function.

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瑞德西韦及其代谢物GS-441524在COVID-19住院患者中的群体药代动力学模型

背景和目的：在确诊为冠状病毒病-2019 （COVID-19）病因的严重急性呼吸综合征冠状病毒-2 （SARS-CoV-2）住院患者中，瑞德西韦及其活性代谢物GS-441524的许可剂量是否达到目标浓度的数据有限。本研究的目的是描述瑞德西韦和GS-441524在COVID-19住院患者中的群体药代动力学，并建立一个模型，为临床使用的剂量优化提供信息。方法：这是一项前瞻性、开放标签、多中心、观察性研究，在澳大利亚四家医院中对确诊为SARS-CoV-2感染的成年人进行了研究。患者给予许可剂量的瑞德西韦。采用超高效液相色谱-质谱联用技术（LC-MS/MS）对多个血浆样品在给药间隔内不同时间的Remdesivir和GS-441524浓度进行定量分析。患者分为药代动力学模型建立组和外部验证组。采用非线性混合效应模型建立群体药代动力学分析。采用蒙特卡罗模拟来描述年龄、肾功能和给药方案对药物浓度的影响。结果：共纳入33例患者（中位年龄70岁，估计肾小球滤过率（eGFR） 80 mL/min/1.73 m2）。两种化合物的药代动力学通过一阶消除的双室模型（每种化合物一个室）充分描述。最终模型中包含的关键协变量是年龄和eGFR。在推荐剂量下，GS-441524的血药浓度超过报道的最低半有效浓度（EC50），较高剂量超过报道的最低90%有效浓度（EC90）。结论：许可的瑞德西韦剂量可能达到GS-441524的目标浓度，但更高的剂量可能会优化结果。剂量调整主要以肾功能为指导。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.