In Silico Prediction of Biopharmaceutical Features of Remdesivir: A Serendipitous Drug for COVID‐19

: Due to the novel nature of the Coronavirus Disease 2019 (COVID-19), there is limited or no standard treatment for it. Remdesivir is the only approved agent for COVID-19, however, there is limited information available about the physicochemical and pharmacokinetic (PK) properties of this drug. The objective of this in silico simulation work was to simulate the biopharmaceutical behavior of remdesivir. The Spatial Data File format structures of remdesivir prodrug and nucleoside core were obtained from the PubChem database to upload on the GastroPlus software 9.7 version. The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor and PKPlus modules were used to simulate physicochemical and PK properties, respectively, in healthy and predisposed patients. Remdesivir’s nucleoside core (GS-441524) was more hydrophilic than the inactive prodrug (GS-5734) with nucleoside core demonstrating better water solubility. Both had low blood brain barrier penetration while GS-5734 predicted to be 100% metabolized by CYP3A4. The bioavailability (Fa%, F%, Cmax, CmaxLiver) of GS-5734 was higher than GS-441524. In addition, there was limited effect of renal function, liver function, weight, or age on the PK profile of remdesivir. GS-5734 (inactive prodrug) appears to be a superior remdesivir derivative due to its hepatic stability, optimum hydrophilic/lipophilic nature, and disposition properties with limited effect of patient physiological conditions.

• Remdesivir was originally developed against Ebola virus but has shown to be somewhat effective against COVID-19.
• Although FDA has approved remdesivir for COVID-19, there is limited information available about its physicochemical and pharmacokinetic (PK) properties.
• The objective of this in silico simulation work was to predict the biopharmaceutical properties of remdesivir.

Introduction: Remdesivir Pharmacological Target
Remdesivir is an adenosine analog prodrug that converts metabolically to GS-441524.GS-441524 is then up taken by infected SARS-CoV-2 lung cells.Intracellularly GS-441524 becomes GS-443902 a nucleoside triphosphate metabolite after a series of phosphorylations.The active nucleoside triphosphate selectively inhibits its pharmacological target viral RNA-dependent RNA polymerase, preventing replication of SARS-CoV-2.• The Spatial Data File format structures of remdesivir prodrug and nucleoside core were obtained from the PubChem database to upload on the GastroPlus software 9.7 version.
• The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor and PKPlus modules were used to simulate physicochemical and PK properties, respectively, in healthy and predisposed patients.
• PK models simulated include:

Results and discussion
Table 5.Preliminary predicted pharmacokinetic parameters of 1-hour IV infusion of 100 mg of GS-441524 (nucleoside core) in different simulated populations.The PKPlus platform was used in a single compartment model.
• GastroPlus software was useful in predicting physicochemical and pharmacokinetic properties remdesivir and its derivatives.
• GS-5734, inactive prodrug was more lipophilic, and expressed a clearance via metabolism.
• GS-441524, nucleoside core was more hydrophilic being eliminated via excretion.
• GS-5734 (inactive prodrug) appears to be a superior remdesivir derivative due to its hepatic stability, optimum hydrophilic/lipophilic nature, and disposition properties with limited effect of patient physiological conditions.
• Potential applications will require additional validation using further in vitro and in vivo studies.
GastroPlus software 9.7 version was provided to S.D. by Simulations Plus, Inc. (Lancaster, CA) as an in-kind research support.

Table 1 .
Preliminary estimation of physicochemical properties of remdesivir using GastroPlus software.

Table 2 .
Preliminary CYP-mediated predicted metabolism and ability to cross blood brain barrier (BBB) of remdesivir determined by ADMET Predictor feature of the GastroPlus software.

Table 3 .
Preliminary predicted pharmacokinetic properties using compartmental PK models.

Table 4 .
Preliminary predicted pharmacokinetic parameters of 1-hour IV infusion of 200 mg remdesivir (GS-5734, inactive prodrug) in different simulated populations.The PKPlus platform was used in a single compartment model.