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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In total, 33 patients were enrolled (median age 70 years, estimated glomerular filtration rate (eGFR) 80 mL\/min\/1.73 m\n                      <jats:sup>2<\/jats:sup>\n                      ). 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\n                      <jats:sub>50<\/jats:sub>\n                      ) with the recommended dosage, and higher dosages exceeded the lowest reported 90%-effective concentration (EC\n                      <jats:sub>90<\/jats:sub>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s40262-025-01496-2","type":"journal-article","created":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T03:37:39Z","timestamp":1745293059000},"page":"743-756","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Population Pharmacokinetic Modelling of Remdesivir and Its Metabolite GS-441524 in Hospitalised Patients with COVID-19"],"prefix":"10.1007","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9101-7577","authenticated-orcid":false,"given":"Darren M.","family":"Roberts","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne L.","family":"Parker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Burke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Peek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane E.","family":"Carland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridin","family":"Murnion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Seah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven C.","family":"Wallis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandra D.","family":"Sumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurabh","family":"Pandey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hergen","family":"Buscher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Byrne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indy","family":"Sandaradura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Bowen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Holz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam G.","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krispin M.","family":"Hajkowicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason A.","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,22]]},"reference":[{"issue":"5","key":"1496_CR1","doi-asserted-by":"publisher","first-page":"1648","DOI":"10.1021\/acs.jmedchem.6b01594","volume":"60","author":"D Siegel","year":"2017","unstructured":"Siegel D, Hui HC, Doerffler E, Clarke MO, Chun K, Zhang L, et al. 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J.A. Roberts would like to acknowledge funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (grant no. APP2007007) and an Investigator Grant (grant no. APP2009736) as well as an Advancing Queensland Clinical Fellowship. This research was supported by The Prince Charles Hospital Common Good Foundation.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"J.A Roberts has served on an advisory board for Gilead and has also received speaking fees. K. M. Hajkowicz has received research grant support from Gilead, served on a Gilead advisory board and received speaking fees from Gilead. All other authors have no conflicts to declare.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of Interest\/Competing Interests"}},{"value":"The study protocol was approved by Human Research Ethics Committees of St Vincent\u2019s Hospital Sydney (2021\/ETH11567), The University of Queensland (2022\/HE00260) and Royal Brisbane and Women\u2019s Hospital (HREC\/2020\/QRBW\/66533).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Informed consent was obtained for all participants in this study.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Informed consent was obtained from all participants in this study.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The data that support the findings of this study are not openly available owing to reasons of sensitivity but are available from the corresponding author upon reasonable request.","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Availability of Data and Material"}},{"value":"Modelling script is included in the Supplementary File and can be made available upon reasonable request.","order":8,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code Availability"}},{"value":"All authors have materially participated in the research and article preparation and have approved the final version for submission.","order":9,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 Contributions"}}]}}