Pharmacokinetics, Mass Balance, Safety, and Tolerability of Obeldesivir in Healthy Participants

Abstract

There is an unmet need for safe and efficacious oral therapies for COVID‐19 with low potential for drug–drug interactions. Obeldesivir is an orally administered nucleoside prodrug that has shown antiviral potency in nonclinical studies against SARS‐CoV‐2 and its circulating variants. Obeldesivir is metabolized to the active nucleoside triphosphate (GS‐443902), which acts as an inhibitor of the SARS‐CoV‐2 RNA‐dependent RNA polymerase, thereby inhibiting viral RNA synthesis. Here, we report the safety, tolerability, and pharmacokinetics from a first‐in‐human, randomized, placebo‐controlled, phase I study following oral administration of obeldesivir and a phase I, open‐label absorption, distribution, metabolism, and excretion study following oral administration of [14C]‐obeldesivir. Overall, obeldesivir was safe and well tolerated at single and multiple doses between 100 and 1,600 mg, with low potential for QT prolongation as assessed by QT‐concentration analysis. The exposures to GS‐441524 increased dose proportionally in the 100–900‐mg dose range. GS‐441524 accumulated by 35% after twice‐daily and 12% after once‐daily dosing for 5 days. Dose‐proportional increases in the intracellular concentration of GS‐443902 were also observed in peripheral blood mononuclar cells. Plasma exposure of GS‐441524 was not significantly altered by food intake. Following oral administration of [14C]‐obeldesivir (500 mg; 100 μCi), the mean cumulative [14C]‐dose recovery was 90.7% with 58.5% in urine and 32.2% in feces. GS‐441524 was the predominant plasma component (90% of 14C‐area under the concentration–time curve) and was primarily eliminated via renal excretion. Collectively, data from these studies support selection of the obeldesivir 350 mg twice‐daily dosing regimen for further evaluation in phase III studies for COVID‐19.