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.
J Antimicrob Chemother
; 75(7): 1772-1777, 2020 07 01.
Article
en En
| MEDLINE
| ID: mdl-32361744
ABSTRACT
BACKGROUND:
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.OBJECTIVES:
The validation of a reliable UHPLC-MS/MS method for remdesivir and GS-441524 quantification in human plasma.METHODS:
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, 2.1â×â50 mm column, with a gradient of water and acetonitrile with 0.05% formic acid. The method was validated using EMA and FDA guidelines.RESULTS:
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.CONCLUSIONS:
This method represents a useful tool for studying remdesivir and GS-441524 clinical pharmacokinetics, particularly during the current COVID-19 outbreak.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Adenosina Monofosfato
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Adenosina Trifosfato
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Cromatografía Líquida de Alta Presión
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Fiebre Hemorrágica Ebola
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Alanina
/
Espectrometría de Masas en Tándem
Tipo de estudio:
Diagnostic_studies
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Guideline
Límite:
Humans
Idioma:
En
Año:
2020
Tipo del documento:
Article