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

Clin Pharmacol Ther. 2024 Nov;116(5):1231-1239. doi: 10.1002/cpt.3337. Epub 2024 Jun 28.

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.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adult
  • Antiviral Agents* / administration & dosage
  • Antiviral Agents* / adverse effects
  • Antiviral Agents* / pharmacokinetics
  • COVID-19
  • COVID-19 Drug Treatment
  • Dose-Response Relationship, Drug
  • Female
  • Healthy Volunteers*
  • Humans
  • Male
  • Middle Aged
  • Prodrugs / administration & dosage
  • Prodrugs / adverse effects
  • Prodrugs / pharmacokinetics
  • SARS-CoV-2 / drug effects
  • Young Adult

Substances

  • Antiviral Agents
  • Prodrugs

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