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Observational Study
. 2022 Jun 21;66(6):e0025422.
doi: 10.1128/aac.00254-22. Epub 2022 Jun 1.

Population Pharmacokinetics of Remdesivir and GS-441524 in Hospitalized COVID-19 Patients

E Leegwater  1   2   3 , D J A R Moes  4 , L B E Bosma  1 , T H Ottens  5 , I M van der Meer  6 , C van Nieuwkoop  6 , E B Wilms  1   2
Affiliations
Observational Study

Population Pharmacokinetics of Remdesivir and GS-441524 in Hospitalized COVID-19 Patients

E Leegwater et al. Antimicrob Agents Chemother. .

Abstract

The objective of this study was to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalized coronavirus disease 2019 (COVID-19) patients. A prospective observational pharmacokinetic study was performed in non-critically ill hospitalized COVID-19 patients with hypoxemia. For evaluation of the plasma concentrations of remdesivir and its metabolite GS-441524, samples were collected on the first day of therapy. A nonlinear mixed-effects model was developed to describe the pharmacokinetics and identify potential covariates that explain variability. Alternative dosing regimens were evaluated using Monte Carlo simulations. Seventeen patients were included. Remdesivir and GS-441524 pharmacokinetics were best described by a one-compartment model. The estimated glomerular filtration rate (eGFR) on GS-441524 clearance was identified as a clinically relevant covariate. The interindividual variability in clearance and volume of distribution for both remdesivir and GS-441524 was high (remdesivir, 38.9% and 47.9%, respectively; GS-441525, 47.4% and 42.9%, respectively). The estimated elimination half-life for remdesivir was 0.48 h, and that for GS-441524 was 26.6 h. The probability of target attainment (PTA) of the in vitro 50% effective concentration (EC50) for GS-441524 in plasma can be improved by shortening the dose interval of remdesivir and thereby increasing the total daily dose (PTA, 51.4% versus 94.7%). In patients with reduced renal function, the metabolite GS-441524 accumulates. A population pharmacokinetic model for remdesivir and GS-441524 in COVID-19 patients was developed. Remdesivir showed highly variable pharmacokinetics. The elimination half-life of remdesivir in COVID-19 patients is short, and the clearance of GS-441524 is dependent on the eGFR. Alternative dosing regimens aimed at optimizing the remdesivir and GS-441524 concentrations may improve the effectiveness of remdesivir treatment in COVID-19 patients.

Keywords: COVID-19; pharmacokinetics; remdesivir.

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Conflict of interest statement

The authors declare a conflict of interest. The Hague Hospital Pharmacy (E.L. and E.B.W.) received a research grant from Gilead Sciences Inc., unrelated to the submitted work. T.H.O. participates in a COVID-19 Digital Advisory Board from Gilead Sciences Inc. All other authors: none to declare.

Figures

FIG 1
FIG 1
Simulated remdesivir concentrations versus time for four dosing regimens. The blue line is the median concentration, and the shaded area is the 95% prediction interval. The red solid line represents the in vitro EC50 in Calu3 2B4 cells, and the red dotted line represents the in vitro EC50 in human airway epithelial cells.
FIG 2
FIG 2
Simulated GS-441524 concentrations versus time for four dosing regimens. The blue line is the median concentration, and the shaded area is the 95% prediction interval. The red line represents the in vitro EC50 in Calu3 2B4 cells, and the red dotted line represents the in vitro EC50 in human airway epithelial cells.
FIG 3
FIG 3
Simulated GS-441524 concentrations versus time for three different estimated glomerular filtration rates using the standard dosing regimen of 200 mg followed by 100 mg every 24 h. The blue line is the median concentration, and the shaded area is the 95% prediction interval. The red line represents the in vitro EC50 in Calu3 2B4 cells, and the red dotted line represents the in vitro EC50 in human airway epithelial cells.
See this image and copyright information in PMC

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