2549 Background: Panobinostat (PAN), a hydroxamic acid derivative, is a potent pan-deacetylase inhibitor, demonstrating anti-tumor activities in a wide variety of preclinical models and showing promising clinical activity. This study elucidates the metabolic and elimination pathways of PAN using [14C]-PAN. Methods: Four patients with advanced cancer received a single oral 20 mg dose of [14C]-PAN (50 μCi). Whole blood, plasma, urine, and feces were collected over 7 days. Total radioactivity was measured in blood, plasma, and excreta by liquid scintillation counting. PAN and its metabolite concentrations in plasma and excreta were measured by LC-MS/MS and HPLC with radiometric detection. Patients were monitored for safety. Results: The single PAN dose was well tolerated with no clinically significant laboratory or ECG abnormalities observed. PAN had a rapid oral absorption [median Tmax 0.8 h (range, 0.5–1 h)] and moderate elimination (median t1/2 31 h). The median t1/2 for blood and plasma radioactivity was 54 and 75 hours, respectively. Mass balance was achieved with ≥87% of the administered radioactivity being recovered in the excreta of all patients after 7 days. 44–77% and 29–51% of the dose was recovered in the feces and urine, respectively. Unchanged PAN accounted for ≤3% of the administered dose in the feces, suggesting good oral absorption. The most prominent metabolic pathways involved modifications of the hydroxamic acid (HA) side chain, to form an amide via reduction, carboxylic acid via either hydrolysis or one- and two-carbon (M1) shortening of the HA side chain. Oxygenation and glucuronidation were also observed. PAN accounted for ≤9% of the total radioactivity AUC. The most abundant circulating metabolites in plasma were the glucuronide of M1 (19%) and carbamoyl glucuronide of PAN (13%). At least 40 metabolites, many at trace levels, were observed circulating in plasma. Conclusions: PAN and its metabolites are equally excreted in the urine and feces. Elimination of PAN is primarily by metabolism via reduction, hydrolysis, oxidation and glucuronidation. The balanced elimination and absence of a single major route of PAN metabolism suggest that clinical drug-drug interactions are unlikely with PAN. [Table: see text]