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
{"title":"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","authors":"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","doi":"10.1007/s40262-025-01496-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objectives: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>In total, 33 patients were enrolled (median age 70 years, estimated glomerular filtration rate (eGFR) 80 mL/min/1.73 m<sup>2</sup>). 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 (EC<sub>50</sub>) with the recommended dosage, and higher dosages exceeded the lowest reported 90%-effective concentration (EC<sub>90</sub>).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"743-756"},"PeriodicalIF":4.6000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064607/pdf/","citationCount":"0","resultStr":"{\"title\":\"Population Pharmacokinetic Modelling of Remdesivir and Its Metabolite GS-441524 in Hospitalised Patients with COVID-19.\",\"authors\":\"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\",\"doi\":\"10.1007/s40262-025-01496-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objectives: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>In total, 33 patients were enrolled (median age 70 years, estimated glomerular filtration rate (eGFR) 80 mL/min/1.73 m<sup>2</sup>). 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 (EC<sub>50</sub>) with the recommended dosage, and higher dosages exceeded the lowest reported 90%-effective concentration (EC<sub>90</sub>).</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":10405,\"journal\":{\"name\":\"Clinical Pharmacokinetics\",\"volume\":\"64 5\",\"pages\":\"743-756\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2025-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064607/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Pharmacokinetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s40262-025-01496-2\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/4/22 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s40262-025-01496-2","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/4/22 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Population Pharmacokinetic Modelling of Remdesivir and Its Metabolite GS-441524 in Hospitalised Patients with COVID-19.
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.
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.
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