Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of Remdesivir, a SARS-CoV-2 Replication Inhibitor

Abstract

Remdesivir (RDV, Veklury ® ) is a once-daily, nucleoside ribonucleic acid polymerase inhibitor of severe acute respiratory syndrome coronavirus 2 replication. Remdesivir has been granted approvals in several countries for use in adults and children hospitalized with severe coronavirus disease 2019 (COVID-19). Inside the cell, remdesivir undergoes metabolic activation to form the intracellular active triphosphate metabolite, GS-443902 (detected in peripheral blood mononuclear cells), and ultimately, the renally eliminated plasma metabolite GS-441524. This review discusses the pre-clinical pharmacology of RDV, clinical pharmacokinetics, pharmacodynamics/concentration-QT analysis, rationale for dose selection for treatment of patients with COVID-19, and drug–drug interaction potential based on available in vitro and clinical data in healthy volunteers. Following single-dose intravenous administration over 2 h of an RDV solution formulation across the dose range of 3–225 mg in healthy participants, RDV and its metabolites (GS-704277and GS-441524) exhibit linear pharmacokinetics. Following multiple doses of RDV 150 mg once daily for 7 or 14 days, major metabolite GS-441524 accumulates approximately 1.9-fold in plasma. Based on pharmacokinetic bridging from animal data and available human data in healthy volunteers, the RDV clinical dose regimen of a 200-mg loading dose on day 1 followed by 100-mg maintenance doses for 4 or 9 days was selected for further evaluation of pharmacokinetics and safety. Results showed high intracellular concentrations of GS-443902 suggestive of efficient conversion from RDV into the triphosphate form, and further supporting this clinical dosing regimen for the treatment of COVID-19. Mathematical drug–drug interaction liability predictions, based on in vitro and phase I data, suggest RDV has low potential for drug–drug interactions, as the impact of inducers or inhibitors on RDV disposition is minimized by the parenteral route of administration and extensive extraction. Using physiologically based pharmacokinetic modeling, RDV is not predicted to be a clinically significant inhibitor of drug-metabolizing enzymes or transporters in patients infected with COVID-19 at therapeutic RDV doses. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-021-00984-5.

Real‐life study on the pharmacokinetic of remdesivir in ICU patients admitted for severe COVID‐19 pneumonia

“…8.1, Certara, NJ, USA) software. Due to the impossibility to perform intensive PK sampling on critical patients, the estimation of elimination t1/2 for GS-441524 was based on two points (period between 15-24 h), assuming a constant t1/2 at this late elimination timings, as reported in previous works [13][14][15] .…”

“…The method was validated following FDA and EMA guidelines, showing contained bias and coefficients of variation (all <15% for both RDV and GS-441524) and good linearity (linear R 2 >0.996) [13][14][15] .…”

Artificial Neural Network Based Study Predicting GS-441524 As Potential Inhibitor of SARS COV-2 Activator Protein Furin: A Polypharmacology Approach

“…Additionally in combination with HCV partner A number of very recent researches are evidencing the importance of GS-441524 as a potent antiviral drug due to its strong binding properties with NSP3 macrodomain and NSP12-NSP8-NSP7 of SARS Cov 2 [34], [35] . It has also been proven that this molecule has very less retention value inside host body as most of the residue is eliminated with urine suspecting no side effect [36] . Amazingly out of the majority of Remdesivir in clinical trial experiments, recovered in urine was found to be in form of GS-441524; whereas only 10% recovered as remdesivir [37], [38] .…”

Remdesivir to treat COVID-19: can dosing be optimized?

“…We develop a PK model to describe the distribution in the body of the remdesivir (RDV) prodrug and its active triphosphate metabolite GS-443902, (RDV-TP) parametrized using data from Humeniuk et al (2020) [15]. We focus on these two components because the metabolic pathway leading from extracellular RDV to intracellular RDV-TP is not yet confirmed [15][16][17]. However, there is consensus that intracellular RDV-TP is the active form of the drug [16][17][18].…”

“…The metabolic pathway leading from extracellular RDV to intracellular RDV-TP is not yet confirmed [15][16][17]. However, there is consensus that intracellular RDV-TP is the active form of the drug [16][17][18]. For the purpose of this study, we therefore a novel PK model to describe the distribution in the body of the remdesivir (RDV) prodrug and its active triphosphate metabolite GS-443902, (RDV-TP), parametrized using data from safety and tolerability investigations reported in Humeniuk et al (2020) [15].…”