title: LC-MS/MS assay for the quantitation of the HDAC inhibitor belinostat and five major metabolites in human plasma.
abstract: The histone deacetylase inhibitor belinostat is being evaluated clinically as a single agent in the treatment of peripheral T-cell lymphomas and in combination with other anticancer agents to treat a wide range of human cancers including acute leukemias and solid tumors. To determine the pharmacokinetics of belinostat in the NCI ODWG liver dysfunction study, we developed and validated an LC-MS/MS assay for the quantitation of belinostat and five major metabolites in 0.05 mL human plasma. After protein precipitation, chromatographic separation was achieved with a Waters Acquity BEH C18 column and a linear gradient of 0.1% formic acid in acetonitrile and water. Detection with an ABI 4000Q mass spectrometer utilized both electrospray positive and negative mode ionization. The assay was linear from 30 to 5000 ng/mL for all six analytes and proved to be accurate (92.0-104.4%) and precise (CV <13.7%), and fulfilled FDA criteria for bioanalytical method validation. We demonstrated the suitability of this assay for measuring parent drug and five major metabolites in plasma from a patient who was administered belinostat IV at a dose of 400 mg/m(2). The LC-MS/MS assay that has been developed will be an essential tool to further define the metabolism and pharmacology of belinostat in the ongoing liver organ dysfunction as well as other studies that investigate belinostat with other anticancer agents.
authors: Molecular Therapeutics Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213-1863, USA.
authors: Brian F
authors: BF
authors: Kiesel
authors: Robert A
authors: RA
authors: Parise
authors: Jette
authors: J
authors: Tjørnelund
authors: Mette K
authors: MK
authors: Christensen
authors: Einars
authors: E
authors: Loza
authors: Hussein
authors: H
authors: Tawbi
authors: Edward
authors: E
authors: Chu
authors: Shivaani
authors: S
authors: Kummar
authors: Jan H
authors: JH
authors: Beumer
mesh_terms: D002853:Chromatography, Liquid / Q000379:methods*; D056572:Histone Deacetylase Inhibitors / Q000032:analysis / Q000493:pharmacokinetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000032:analysis / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013449:Sulfonamides / Q000032:analysis / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; C487081:belinostat
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