Hybrid physiologically-based pharmacokinetic model for remdesivir: Application to SARS-CoV-2

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Virology
• Computational Biology

Background:

• Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) causes COVID-19, necessitating effective antiviral treatments.
• Remdesivir (RDV) is an antiviral prodrug requiring intracellular conversion to its active form, triphosphate nucleoside (TN).
• Understanding intracellular TN concentrations in target tissues like the lungs is crucial for optimizing RDV therapy.

Purpose of the Study:

• To develop a physiologically-based pharmacokinetic (PBPK) model to characterize RDV and TN disposition in humans.
• To assess intracellular TN concentrations in the lungs under various dosing regimens.
• To evaluate the effectiveness of current RDV treatment regimens based on predicted lung TN levels.

Main Methods:

• A hybrid PBPK model was constructed using existing human data, featuring two-compartment tissue models (extracellular and intracellular).
• The intracellular compartments incorporated a detailed metabolic model for RDV conversion to TN.
• Global sensitivity analyses and Monte-Carlo simulations were performed to identify key parameters influencing TN profiles.

Main Results:

• The PBPK model successfully characterized RDV and TN disposition.
• Sensitivity analyses identified critical parameters impacting intracellular TN concentrations in peripheral blood mononuclear cells and lungs.
• Simulated multiple-dose regimens predicted minimum lung intracellular TN concentrations between 4 µM and 9 µM.

Conclusions:

• Predicted lung intracellular TN concentrations suggest current Remdesivir regimens are effective against SARS-CoV-2, based on in vitro efficacy data.
• The developed PBPK model provides a valuable tool for exploring drug disposition and optimizing therapeutic strategies for RDV.
• The model can be further expanded to incorporate pharmacodynamic aspects for more comprehensive treatment analysis.