Simulation of Remdesivir Pharmacokinetics and Its Drug Interactions
Author:
Deb S, Reeves AA.
Date: 5 June 2021
Abstract:
ABSTRACT – Purpose: Remdesivir, a drug originally developed against Ebola virus, is currently recommended
for patients hospitalized with coronavirus disease of 2019 (COVID-19). In spite of United States Food and Drug
Administration’s recent assent of remdesivir as the only approved agent for COVID-19, there is limited
information available about the physicochemical, metabolism, transport, pharmacokinetic (PK), and drug-drug
interaction (DDI) properties of this drug. The objective of this in silico simulation work was to simulate the
biopharmaceutical and DDI behavior of remdesivir and characterize remdesivir PK properties in special
populations which are highly affected by COVID-19.
Methods: The Spatial Data File format structures of
remdesivir prodrug (GS-5734) and nucleoside core (GS-441524) were obtained from the PubChem database to
upload into the GastroPlus software 9.8 version (Simulations Plus Inc., USA). The Absorption, Distribution,
Metabolism, Excretion and Toxicity (ADMET) Predictor and PKPlus modules of GastroPlus were used to simulate
physicochemical and PK properties, respectively, in healthy and predisposed patients. Physiologically based
pharmacokinetic (PBPK) modeling of GastroPlus was used to simulate different patient populations based on age,
weight, liver function, and renal function status. Subsequently, these data were used in the Drug-Drug Interaction
module to simulate drug interaction potential of remdesivir with other COVID-19 drug regimens and with agents
used for comorbidities.
Results: Remdesivir nucleoside core (GS-441524) is more hydrophilic than the inactive
prodrug (GS-5734) with nucleoside core demonstrating better water solubility. GS-5734, but not GS-441524, is
predicted to be metabolized by CYP3A4. Remdesivir is bioavailable and its clearance is achieved through hepatic
and renal routes. Differential effects of renal function, liver function, weight, or age were observed on the PK
profile of remdesivir. DDI simulation study of remdesivir with perpetrator drugs for comorbidities indicate that
carbamazepine, phenytoin, amiodarone, voriconazole, diltiazem, and verapamil have the potential for strong
interactions with victim remdesivir, whereas agents used for COVID-19 treatment such as chloroquine and
ritonavir can cause weak and strong interactions, respectively, with remdesivir.
Conclusions: GS-5734 (inactive
prodrug) appears to be a superior remdesivir derivative due to its hepatic stability, optimum hydrophilic/lipophilic
balance, and disposition properties. Remdesivir disposition can potentially be affected by different physiological
and pathological conditions, and by drug interactions from COVID-19 drug regimens and agents used for
comorbidities
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