Pharmacokinetics, metabolism, and excretion of ^sup 14^C-labeled belinostat in patients with recurrent or progressive malignancies

• Published in: Investigational new drugs Vol. 34; no. 2; p. 193
• Main Authors: Calvo, Emiliano, Reddy, Guru, Boni, Valentina, García-cañamaque, Lina, Song, Tao, Tjornelund, Jette, Choi, Mi Rim, Allen, Lee F
• Format: Journal Article
• Language: English
• Published: New York Springer Nature B.V 01-04-2016
• Subjects: Apoptosis; Cancer; Cancer therapies; Cell growth; Clinical trials; Drug dosages; Enzymes; Epigenetics; FDA approval; Feces; Gene expression; Inhibitor drugs; Lymphoma; Metabolism; Metabolites; Patients; Pharmaceutical sciences; Pharmacokinetics; Plasma; Radioactivity; Signal transduction; Studies; Urine; Europe
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-015-0321-8

Belinostat, a potent pan-inhibitor of histone deacetylase (HDAC) enzymes, is approved in the United States (US) for relapsed/refractory peripheral T-cell lymphoma. In nonclinical studies, bile and feces were identified as the predominant elimination routes (5070 %), with renal excretion accounting for ~3050 %. A Phase 1 human mass balance study was conducted to identify species-dependent variations in belinostat metabolism and elimination. Patients received a single 30-min intravenous(IV) infusion of 14C-labeled belinostat (1500 mg). Venous blood samples and pooled urine and fecal samples were evaluated using liquid chromatography - tandem mass spectroscopy for belinostat and metabolite concentrations pre-infusion through 7 days post-infusion. Total radioactivity was determined using liquid scintillation counting. Continued treatment with nonradiolabled belinostat (1000 mg/m2 on Days 15 every 21 days) was permitted. Belinostat was extensively metabolized and mostly cleared from plasma within 8 h (N = 6), indicating that metabolism is the primary route of elimination. Systemic exposure for the 5 major metabolites was >20 % of parent, with belinostat glucuronide the predominant metabolite. Mean recovery of radioactive belinostat was 94.5 % 4.0 %, with the majority excreted within 48 and 96 h in urine and feces, respectively. Renal elimination was the principal excretion route (mean 84.8 % 9.8 % of total dose); fecal excretion accounted for 9.7 % 6.5 %. Belinostat was well tolerated, with mostly mild to moderate adverse events and no treatment-related severe/serious events. Mass balance was achieved (~95 % mean recovery), with metabolism identified as the primary route of elimination. Radioactivity was predominantly excreted renally as belinostat metabolites.