Preclinical pharmacokinetics and in vitro activity of ON 01910.Na, a novel anti-cancer agent

Abstract

ON 01910.Na is a novel targeted anti-cancer agent under clinical investigation in Phase I and II trials. The purpose of this research was to evaluate the pharmacokinetic profile of ON 01910.Na across several species, and to evaluate the effects of protein binding and duration of exposure on its in vitro cytotoxic activity. Data were collated from several preclinical investigations, where the plasma disposition and tissue distribution of ON 01910.Na were assessed after administration (10-150 mg/kg, IP or IV) to several species (mouse, rat, and dog). Plasma protein binding was assessed using ultrafiltration. Cytotoxic activity of ON 01910.Na was determined in DU145 cells, and activity was correlated to unbound drug concentration and the duration of exposure. ON 01910.Na exhibits extensive plasma protein binding and the compound displays rapid elimination from the circulation in all three animal species (t(1/2) range 0.404-0.870 h). Tissue distribution studies in mice revealed highest drug accumulation in the liver, followed by the kidneys. ON 01910.Na is not extensively metabolized in vivo and urinary excretion is predominant at higher doses. ON 01910.Na cytotoxicity in DU145 cells was adversely affected by protein binding in the incubation medium. Drug cytotoxicity was greatly enhanced upon extending the duration of exposure at reduced drug concentrations. Due to the short half-life and rapid clearance of the drug, administration of ON 01910.Na by continuous IV infusion is a likely treatment option for cancer patients.