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

Investigational New Drugs
Emiliano CalvoLee F Allen

Abstract

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 (50-70%), with renal excretion accounting for ~30-50%. 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 (i.v.) infusion of (14)C-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/m(2) on Days 1-5 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 belino...Continue Reading

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Citations

Jan 10, 2019·Molecular Pharmacology·Kodye L AbbottSatyanarayana R Pondugula
Sep 8, 2019·Investigational New Drugs·Gabriela C SegatJoão B Calixto
Oct 7, 2017·Journal of Medicinal Chemistry·Paul HermantRebecca Deprez-Poulain
Oct 13, 2021·Chembiochem : a European Journal of Chemical Biology·Eron Saxon, Xiaohua Peng

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