Population pharmacokinetic modeling of GS‐441524, the active metabolite of remdesivir, in Japanese COVID‐19 patients with renal dysfunction

Abstract

Remdesivir, a prodrug of the nucleoside analog GS‐441524, plays a key role in the treatment of coronavirus disease 2019 (COVID‐19). However, owing to limited information on clinical trials and inexperienced clinical use, there is a lack of pharmacokinetic (PK) data in patients with COVID‐19 with special characteristics. In this study, we aimed to measure serum GS‐441524 concentrations and develop a population PK (PopPK) model. Remdesivir was administered at a 200 mg loading dose on the first day followed by 100 mg from day 2, based on the package insert, in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min. In total, 190 concentrations from 37 Japanese patients were used in the analysis. The GS‐441524 trough concentrations were significantly higher in the eGFR less than 60 ml/min group than in the eGFR greater than or equal to 60 ml/min group. Extracorporeal membrane oxygenation in four patients hardly affected the total body clearance (CL) and volume of distribution ( V d ) of GS‐441524. A one‐compartment model described serum GS‐441524 concentration data. The CL and V d of GS‐441524 were significantly affected by eGFR readjusted by individual body surface area and age, respectively. Simulations proposed a dose regimen of 200 mg on day 1 followed by 100 mg once every 2 days from day 2 in patients with an eGFR of 30 ml/min or less. In conclusion, we successfully established a PopPK model of GS‐441524 using retrospectively obtained serum GS‐441524 concentrations in Japanese patients with COVID‐19, which would be helpful for optimal individualized therapy of remdesivir.

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

“…Efforts to fit more complex models to the data resulted in parameter estimates with high residual errors, which could be a result of the limited sample size in this study. Nevertheless, the developed one-compartment model showed good resemblance between the predicted and measured concentrations of remdesivir and GS-441524 and is in line with the results of Sukeishi et al for GS-441524 ( 21 ).…”

“…However, the lower elimination half-life could also be related to differences in study populations or study procedures. GS-441524 clearance in COVID-19 patients was higher than that previously reported (27.6 L/h versus 11.8 L/h), a possible result of the higher median eGFR, differences in ethnicity or the severity of disease, or the lack of remdesivir concentration data in the study population ( 21 ). The volume of distribution was larger for remdesivir and GS-441524 than that in healthy individuals, which can be explained by the high BMI of the patients in the study population or potentially disease- or treatment-related factors.…”

“…The optimal dose leading to the maximal antiviral efficacy of remdesivir in humans is currently unknown, but modeling and simulation studies suggest that the current dosing regimen might be suboptimal ( 14 , 15 ). These studies were performed using pharmacokinetic data from healthy individuals, whereas studies regarding the pharmacokinetics of remdesivir in COVID-19 patients are limited to case series with scarce sampling schedules and a single pharmacokinetic study with only GS-441524 concentrations ( 16 – 21 ).…”

Biotransformation and transplacental transfer of the anti-viral remdesivir and predominant metabolite, GS-441524 in pregnant rats

“… 26 The high volume of distribution of GS-441524 (6.36 L/kg) is consistent with this interpretation. 27 Upon comparison of differences in pharmacokinetic characteristics in plasma between humans and rats, despite different routes of drug administration, similar remdesivir and GS-441524 pharmacokinetics characteristics were observed. Remdesivir followed a rapid decline 28 and the absorption of GS-441524 appeared at the second time-point, with a slow elimination phase.…”

Remdesivir for COVID‐19 pneumonia in patients with severe chronic kidney disease: A Case series and review of the literature

“… 11 Contrary to the precautionary advice, for patients with eGFR <30 some reported studies recommend dose adjustment rather than precautionary limits. 12 On the other hand, animal studies demonstrated potential, beneficial, renal effects in reversing obstructive renal fibrosis. 13 Of note, such cohort of patients with chronic kidney disease at significant risks of acquisition and complications of COVID‐19 disease as highlighted from multiple observational studies.…”