Journal Article

Pharmacokinetics and Metabolism of Broad-Spectrum Antivirals Remdesivir and Obeldesivir with a Consideration to Metabolite GS-441524: Same, Similar, or Different?

Ip, Carmen, Le, Hoa, Leung, Jennifer, Pitts, Jared, Mackman, Richard L., Zhao, Xiaofeng, Murray, Bernard, Kim, Cynthia, Babusis, Darius, Yang, Jesse, Geng, Guoju, Kozon, Nathan, Siegel, Dustin S., Kalla, Rao, Subramanian, Raju, Bannister, Roy, Bilello, John P.

2025

Overview

RNA viruses with pandemic potential pose a significant global health risk. The adenosine nucleoside analog GS-441524 is metabolized to its active GS-443902 triphosphate metabolite to inhibit a broad spectrum of RNA viruses. Intravenous (IV) remdesivir (RDV) and oral obeldesivir (ODV) are phosphoramidate and isobutyryl-ester prodrugs of GS-441524, respectively. Following administration, both RDV and ODV show rapid and broad tissue distribution, form the same GS-443902 metabolite in target tissues, and demonstrate promising in vivo efficacy across several RNA virus infection models. In an African green monkey SARS-CoV-2 infection model, respective RDV and ODV treatments yielded similar antiviral efficacy. Here, we compare the in vitro and in vivo pharmacokinetics (PK) and metabolism of RDV and ODV to highlight both similarities and differences in their absorption, metabolism, distribution, and excretion profiles. The distinct route of administration and metabolic fate of each prodrug produced in vivo PK and metabolism profiles with differential GS-441524 to tissue GS-443902 relationships, thereby supporting alternate methods for predicting human efficacious doses. Overall, a metabolism-directed prodrug design enabled optimized delivery of the identical active GS-443902 metabolite through different routes of administration, supporting broader applications of the same nucleoside analog across an expanded spectrum of potential antiviral indications.

• Publisher: MDPI AG,MDPI
• Subject: Adenosine / Adenosine - analogs & derivatives / Adenosine - metabolism / Adenosine - pharmacokinetics / Adenosine Monophosphate - analogs & derivatives / Adenosine Monophosphate - metabolism / Adenosine Monophosphate - pharmacokinetics / Alanine - analogs & derivatives / Alanine - metabolism / Alanine - pharmacokinetics / Animals / Antiviral agents / Antiviral Agents - administration & dosage / Antiviral Agents - metabolism / Antiviral Agents - pharmacokinetics / antivirals / Chlorocebus aethiops / COVID-19 / COVID-19 - virology / COVID-19 Drug Treatment / Disease Models, Animal / Dosage and administration / Ebola virus / Enzymes / GS-441524 / GS-443902 / Health aspects / Humans / Metabolism / Metabolites / Nucleoside analogs / obeldesivir / Pandemics / Permeability / Pharmacokinetics / Pharmacology, Experimental / Phosphorylation / Plasma / Prodrugs / Prodrugs - pharmacokinetics / Public health / remdesivir / Respiratory syncytial virus / RNA viruses / SARS-CoV-2 - drug effects / Severe acute respiratory syndrome coronavirus 2 / Tissue Distribution / Vero Cells / Viruses