Characterizing the disposition, metabolism, and excretion of an orally active pan-deacetylase inhibitor, panobinostat, via trace radiolabeled 14C material in advanced cancer patients

Abstract

Elucidating the metabolic profile of anticancer agent panobinostat is essential during drug development. Disposition, metabolism, and excretion profiles were characterized using trace radiolabeled (14)C-panobinostat in four patients with advanced cancer. Oral (14)C-panobinostat was administered and serial blood, plasma, and excreta samples were collected up to 7 days postdose for radioactivity and pharmacokinetic analyses. Metabolites in plasma and excreta were profiled using liquid chromatography (LC) with radiometric detection, and their structures elucidated using LC-tandem mass spectrometry. Radioactivity (≥87 %) was recovered in excreta within 7 days: 44-77 % dose recovery in feces and 29-51 % in urine. Circulating radioactivity was localized in plasma, with minor partitioning to blood. Minimal recovery in feces (<3.5 % of dose) suggested near-complete oral absorption. Maximum concentrations (median, 21.2 ng/mL; range, 13.4-41.5 ng/mL) were achieved within 1 h, and median (range) terminal half-life, apparent oral, and renal clearance was 30.7 h (27.6-33.2 h), 209 L/h (114-248 L/h), and 3.20 L/h (2.4-5.5 L/h), respectively. Approximately 40 metabolites were circulating in plasma, with biotransformation occurring primarily at the hydroxamic acid side chain and ethyl-methyl indole moiety. Metabolites derived from modification of the hydroxamic acid side chain were inactive for deacetylase inhibition. Panobinostat and its metabolites were excreted in similar amounts through the kidneys and liver with good dose recovery. Panobinostat was rapidly absorbed and cleared primarily through metabolism. Over half of its clearance was attributed to non-CYP-mediated pathways. Thus, CYP-mediated drug-drug interactions with panobinostat are predicted to be minor.