Safety, Pharmacokinetics, and Cardiodynamics of CMS121, a Novel Small Molecule Fisetin Derivative with Neuroprotective Properties, in Phase 1 Healthy Adult Volunteers

The safety, tolerability, pharmacokinetics, age-related effects of single (SD) and repeat (RD) doses of CMS121, a novel small molecule fisetin derivative, were evaluated in healthy adult volunteers. The effects of food were also evaluated in healthy young adult subjects. SD of up to 1800 mg or RD up to 900 mg/day for 7 days was generally well tolerated, with the majority of TEAEs mild in severity. Generally, the pharmacokinetics of CMS121 and its metabolites were well characterized and increased in a dose-proportional or slightly greater than dose-proportional manner across the range of doses assessed. CMS121-C2 metabolite appears to contribute the most to the presence of the molar-equivalent CMS121 in plasma than the parent compound or the other metabolites (i.e. CMS121-C1 and CMS121-C3). Urinary excretion of CMS121 metabolites was minimal, implying urinary excretion may not be a major clearance route by which CMS121 is eliminated after oral dosing. There is a significant effect of age on the pharmacokinetics of CMS121 and its metabolites, with higher systemic exposures to CMS121 and its metabolites and longer terminal elimination half-lives in elderly subjects. Systemic exposures to CMS121 were higher in the fed state by approximately 50%.