Cargando…

Interpatient variability in the pharmacokinetics of remdesivir and its main metabolite GS-441524 in treated COVID-19 subjects

BACKGROUND: Remdesivir is the first antiviral drug against SARS-CoV-2 approved for use in COVID-19 patients. OBJECTIVES: 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 a...

Descripción completa

Detalles Bibliográficos
Autores principales: Tempestilli, Massimo, Ascoli Bartoli, Tommaso, Benvenuto, Domenico, Stazi, Giulia Valeria, Marchioni, Luisa, Nicastri, Emanuele, Agrati, Chiara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9384469/
https://www.ncbi.nlm.nih.gov/pubmed/35848782
http://dx.doi.org/10.1093/jac/dkac234
Descripción
Sumario:BACKGROUND: Remdesivir is the first antiviral drug against SARS-CoV-2 approved for use in COVID-19 patients. OBJECTIVES: 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. METHODS: Inpatients affected by SARS-CoV-2 infections, undergoing standard-dose remdesivir treatment, were prospectively enrolled. Blood samples were collected on day 4, immediately after (C(0)) and at 1 h (C(1)) and 24 h (C(24)) after infusion. Remdesivir and GS-441524 concentrations were measured using a validated UHPLC-MS/MS method and the AUC(0–24) 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. RESULTS: Eighty-five patients were included. The mean (CV%) values of remdesivir were: C(0) 2091 (99.1%) ng/mL, C(1) 139.7 (272.4%) ng/mL and AUC(0–24) 2791 (175.7%) ng·h/mL. The mean (CV%) values of GS-441524 were: C(0) 90.2 (49.5%) ng/mL, C(1) 104.9 (46.6%) ng/mL, C(24) 58.4 (66.9) ng/mL and AUC(0–24) 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. CONCLUSIONS: 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.