Development and validation of a UHPLC-MS/MS method for quantification of the prodrug remdesivir and its metabolite GS-441524: a tool for clinical pharmacokinetics of SARS-CoV-2/COVID-19 and Ebola virus disease



Avataneo, Valeria, de Nicolò, Amedeo, Cusato, Jessica, Antonucci, Miriam, Manca, Alessandra, Palermiti, Alice, Waitt, Catriona ORCID: 0000-0003-0134-5855, Walimbwa, Stephen, Lamorde, Mohammed, di Perri, Giovanni
et al (show 1 more authors) (2020) Development and validation of a UHPLC-MS/MS method for quantification of the prodrug remdesivir and its metabolite GS-441524: a tool for clinical pharmacokinetics of SARS-CoV-2/COVID-19 and Ebola virus disease. Journal of Antimicrobial Chemotherapy.

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Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Remdesivir has received significant attention for its potential application in the treatment of COVID-19, caused by SARS-CoV-2. Remdesivir has already been tested for Ebola virus disease treatment and found to have activity against SARS and MERS coronaviruses. The remdesivir core contains GS-441524, which interferes with RNA-dependent RNA polymerases alone. In non-human primates, following IV administration, remdesivir is rapidly distributed into PBMCs and converted within 2 h to the active nucleoside triphosphate form, while GS-441524 is detectable in plasma for up to 24 h. Nevertheless, remdesivir pharmacokinetics and pharmacodynamics in humans are still unexplored, highlighting the need for a precise analytical method for remdesivir and GS-441524 quantification.</jats:p> </jats:sec> <jats:sec> <jats:title>Objectives</jats:title> <jats:p>The validation of a reliable UHPLC-MS/MS method for remdesivir and GS-441524 quantification in human plasma.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Remdesivir and GS-441524 standards and quality controls were prepared in plasma from healthy donors. Sample preparation consisted of protein precipitation, followed by dilution and injection into the QSight 220 UHPLC-MS/MS system. Chromatographic separation was obtained through an Acquity HSS T3 1.8 μm, 2.1 × 50 mm column, with a gradient of water and acetonitrile with 0.05% formic acid. The method was validated using EMA and FDA guidelines.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Analyte stability has been evaluated and described in detail. The method successfully fulfilled the validation process and it was demonstrated that, when possible, sample thermal inactivation could be a good choice in order to improve biosafety.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>This method represents a useful tool for studying remdesivir and GS-441524 clinical pharmacokinetics, particularly during the current COVID-19 outbreak.</jats:p> </jats:sec>

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 18 May 2020 09:50
Last Modified: 09 Jan 2021 02:10
DOI: 10.1093/jac/dkaa152
URI: https://livrepository.liverpool.ac.uk/id/eprint/3086550