Whole Body PBPK Modeling of Remdesivir and Its Metabolites to Aid in Estimating Active Metabolite Exposure in the Lung and Liver in Patients With Organ Dysfunction

Abstract

Remdesivir (RDV) is the first drug approved by the US Food and Drug Administration (FDA) for the treatment of coronavirus disease 2019 (COVID‐19) in certain patients requiring hospitalization. As a nucleoside analogue prodrug, RDV undergoes intracellular multistep activation to form its pharmacologically active species, GS‐443902, which is not detectable in the plasma. A question arises that whether the observed plasma exposure of RDV and its metabolites would correlate with or be informative about the exposure of GS‐443902 in tissues. A whole body physiologically‐based pharmacokinetic (PBPK) modeling and simulation approach was utilized to elucidate the disposition mechanism of RDV and its metabolites in the lungs and liver and explore the relationship between plasma and tissue pharmacokinetics (PK) of RDV and its metabolites in healthy subjects. In addition, the potential alteration of plasma and tissue PK of RDV and its metabolites in patients with organ dysfunction was explored. Our simulation results indicated that intracellular exposure of GS‐443902 was decreased in the liver and increased in the lungs in subjects with hepatic impairment relative to the subjects with normal liver function. In subjects with severe renal impairment, the exposure of GS‐443902 in the liver was slightly increased, whereas the lung exposure of GS‐443902 was not impacted. These predictions along with the organ impairment study results may be used to support decision making regarding the RDV dosage adjustment in these patient subgroups. The modeling exercise illustrated the potential of whole body PBPK modeling to aid in decision making for nucleotide analogue prodrugs, particularly when the active metabolite exposure in the target tissues is not available.

Prediction for optimal dosage of pazopanib under various clinical situations using physiologically based pharmacokinetic modeling

“…Currently, these parameter changes have been applied to multiple PBPK models (see Supplementary Table S4 ). However, most published papers for PBPK models of hepatic impairment have not taken into account absorption changes between impaired and normal hepatic function ( Morcos et al, 2018 ; Gerner and Scherf-Clavel, 2021 ; Fan et al, 2022 ).…”

A population pharmacokinetic model of remdesivir and its major metabolites based on published mean values from healthy subjects

“…Here we assume that lung epithelial cell exposure is close to plasma exposure. However, PBPK modeling predicts that lung concentrations of GS-441524 are several-fold lower than plasma concentration and that GS-441524 plasma concentrations would not be useful to predict lung exposure of the active metabolite GS-443902 (Fan et al 2021 ).…”

“…A non-compartmental description of data in healthy volunteers has been published and serves as the basis for the present evaluation (Humeniuk et al 2020 ). Several bottom-up approaches using physiologically based pharmacokinetic models have recently been reported (Deb and Reeves 2021 ; Fan et al 2021 ; Humeniuk et al 2021b ; Gallo 2021 ), of which the most recent one was generated by scientists of the U.S. Food and Drug Administration (FDA) (Fan et al 2021 ). Such models are very useful but in part are based on assumptions that remain to be verified, and occasionally use “optimization” of some of their predefined parameters, with no other reason than that simulations should match the observed data.…”

Physiologically‐based pharmacokinetic modeling of remdesivir and its metabolites in pregnant women with COVID‐19

“…The Open Systems Pharmacology software suite (Version 10) including PK‐Sim® and MoBi® was used for PBPK modeling. Here, a recently published PBPK model for nonpregnant adults 9 was translated to pregnancy following a previously described workflow. 10 The general adult model was transferred to MoBi®, where the standard model structure was replaced by the pregnancy model structure.…”

“…The objectives of this study were to translate a previously published nonpregnant PBPK model for RDV 9 to pregnancy and evaluate the model performance with publicly available clinical PK data in pregnant women with COVID‐19. 8…”