Publication date: Jun 10, 2025

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.

Open Access PDF

Semantics

Original Article