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- Title
Interpatient variability in the pharmacokinetics of remdesivir and its main metabolite GS-441524 in treated COVID-19 subjects.
- Authors
Tempestilli, Massimo; Bartoli, Tommaso Ascoli; Benvenuto, Domenico; Stazi, Giulia Valeria; Marchioni, Luisa; Nicastri, Emanuele; Agrati, Chiara; Ascoli Bartoli, Tommaso
- Abstract
<bold>Background: </bold>Remdesivir is the first antiviral drug against SARS-CoV-2 approved for use in COVID-19 patients.<bold>Objectives: </bold>To study the pharmacokinetic inter-individual variability of remdesivir and its main metabolite GS-441524 in a real-world setting of COVID-19 inpatients and to identify possible associations with different demographic/biochemical variables.<bold>Methods: </bold>Inpatients affected by SARS-CoV-2 infections, undergoing standard-dose remdesivir treatment, were prospectively enrolled. Blood samples were collected on day 4, immediately after (C0) and at 1 h (C1) and 24 h (C24) after infusion. Remdesivir and GS-441524 concentrations were measured using a validated UHPLC-MS/MS method and the AUC0-24 was calculated. At baseline, COVID-19 severity (ICU or no ICU), sex, age, BMI and renal and liver functions were assessed. Transaminases and estimated glomerular filtration rate (e-GFR) were also evaluated during treatment. Linear regression, logistic regression and multiple linear regression tests were used for statistical comparisons of pharmacokinetic parameters and variables.<bold>Results: </bold>Eighty-five patients were included. The mean (CV%) values of remdesivir were: C0 2091 (99.1%) ng/mL, C1 139.7 (272.4%) ng/mL and AUC0-24 2791 (175.7%) ng·h/mL. The mean (CV%) values of GS-441524 were: C0 90.2 (49.5%) ng/mL, C1 104.9 (46.6%) ng/mL, C24 58.4 (66.9) ng/mL and AUC0-24 1976 (52.6%) ng·h/mL. The multiple regression analysis showed that age (P < 0.05) and e-GFR (P < 0.01) were independent predictors of GS-441524 plasma exposure.<bold>Conclusions: </bold>Our results showed a high interpatient variability of remdesivir and GS-441524 likely due to both age and renal function in COVID-19 inpatients. Further research is required to understand whether the pharmacokinetics of remdesivir and its metabolites may influence drug-related efficacy or toxic effect.
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2022, Vol 77, Issue 10, p2683
- ISSN
0305-7453
- Publication type
Article
- DOI
10.1093/jac/dkac234