Jesse Yang

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.

Remdesivir (RDV) is a nucleotide analog prodrug with demonstrated clinical benefit in patients with coronavirus disease 2019 (COVID-19). In October 2020, the U.S. FDA approved intravenous RDV as the first treatment for hospitalized COVID-19 patients. Furthermore, RDV has been approved or authorized for emergency use in more than 50 countries. To make RDV more convenient for nonhospitalized patients earlier in disease, alternative routes of administration are being evaluated. Here, we investigated the pharmacokinetics and efficacy of RDV administered by head dome inhalation in African green monkeys (AGM). Relative to an intravenous administration of RDV at 10 mg/kg, an about 20-fold lower dose administered by inhalation produced comparable concentrations of the pharmacologically active triphosphate in lower respiratory tract tissues. Distribution of the active triphosphate into the upper respiratory tract was also observed after inhaled RDV exposure. Inhalation RDV dosing resulted in lower systemic exposures to RDV and its metabolites as compared with intravenous RDV dosing. An efficacy study with repeated dosing of inhaled RDV in an AGM model of SARS-CoV-2 infection demonstrated reductions in viral replication in bronchoalveolar lavage fluid and respiratory tract tissues compared with placebo. Efficacy was observed with inhaled RDV administered once daily at a pulmonary deposited dose of 0.35 mg/kg beginning about 8 hours after infection. Moreover, the efficacy of inhaled RDV was similar to that of intravenous RDV administered once at 10 mg/kg followed by 5 mg/kg daily in the same study. Together, these findings support further clinical development of inhalation RDV.