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Cancer Chemother Pharmacol (2012) 70:513522
DOI 10.1007/s00280-012-1940-9
ORIGINAL ARTICLE
Characterizing the disposition, metabolism, and excretionof an orally active pan-deacetylase inhibitor, panobinostat,via trace radiolabeled 14C material in advanced cancer patients
Sally Clive Margaret M. Woo Thomas Nydam
Lindsay Kelly Margaret Squier Mark Kagan
Received: 8 March 2012 / Accepted: 23 July 2012 / Published online: 5 August 2012 Springer-Verlag 2012
AbstractPurpose Elucidating the metabolic prole of anticancer agent panobinostat is essential during drug development. Disposition, metabolism, and excretion proles were characterized using trace radiolabeled 14C-panobinostat in four patients with advanced cancer.
Methods Oral 14C-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 proled using liquid chromatography (LC) with radiometric detection, and their structures elucidated using LCtandem mass spectrometry.
Results Radioactivity (C87 %) was recovered in excreta within 7 days: 4477 % dose recovery in feces and 2951 % 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, 13.441.5 ng/mL) were achieved within 1 h, and median (range) terminal half-life, apparent oral, and renal clearance was 30.7 h(27.633.2 h), 209 L/h (114248 L/h), and 3.20 L/h(2.45.5 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 modication of the hydroxamic acid side chain were inactive for deacetylase inhibition.
Conclusions 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 drugdrug interactions with panobinostat are predicted to be minor.
Keywords Disposition Metabolism Excretion
Panobinostat DACi
Introduction
Panobinostat, a hydroxamic acid derivative, is a potent, orally active class I/II/IV pan-deacetylase inhibitor (pan-DACi) with antitumor activity within low nanomolar range. Increased deacetylase (DAC) activity is associated with survival of malignant cells, partly through reduced expression of pro-apoptotic genes and up-regulated transcription of anti-apoptotic genes [1, 2]. Panobinostats clinical efcacy has been shown in various solid tumor and hematologic malignancies and has become increasingly important...