title: Development and validation of a sensitive HPLC-MS/MS method for determination of chidamide (epidaza), a new benzamide class of selective histone deacetylase inhibitor, in human plasma and its clinical application.
abstract: Chidamide (epidaza), a new oral isotype-selective histone deacetylase inhibitor (HDACi), which is just approved in China for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in December 2014, is the first listed benzamide class of HDACi in the world, and is currently undergoing global clinical trials for solid tumor treatments. Here, we report a sensitive, rapid and robust HPLC-MS/MS method for determination of chidamide in human plasma. Plasma sample was subjected to a simple acetonitrile protein precipitation containing MS-275 used as an internal standard (IS). Chromatography was performed on a Hypersil GOLD C18 analytical column, using a gradient methanol/water mobile phase containing 0.1% formic acid. A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the positive-ion mode. Selected reaction monitoring (SRM) using the precursor/ product transitions (m/z) of 391.1/265.1 for chidamide and 377.1/359.2 for IS were used for quantification, respectively. Good linearity was obtained in the range of 1-1000ng/mL. The method gave R.S.D.% values for precision always lower than 13.8% and R.E.% values for accuracy between -3.7 and 9.1%. In addition, the specificity, recovery, stability and matrix effect were satisfactory too. The method is now being successfully applied to plasma samples as part of an ongoing chidamide phase Ib clinical trial in patients with solid tumors, and had demonstrated consistent AUClast and t1/2 results with the published phase I pharmacokinetic data, which was also analyzed by this method, thus further confirming the reproducibility and accuracy during its clinical application. Considering the excellent performance of this method, it will continue being utilized for future clinical developments of chidamide and for routine monitoring of plasma exposure of chidamide during its clinical therapy.
authors.affiliation: State Key Laboratory of Drug Metabolism and Pharmacokinetics, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, 27, Taiping Road, Haidian District, Beijing 100850, China.
authors.forename: Ruolan
authors.initials: R
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Drug Metabolism and Pharmacokinetics, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, 27, Taiping Road, Haidian District, Beijing 100850, China.
authors.forename: Taoyun
authors.initials: T
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Drug Metabolism and Pharmacokinetics, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, 27, Taiping Road, Haidian District, Beijing 100850, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Drug Metabolism and Pharmacokinetics, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, 27, Taiping Road, Haidian District, Beijing 100850, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gan
authors.affiliation: State Key Laboratory of Drug Metabolism and Pharmacokinetics, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, 27, Taiping Road, Haidian District, Beijing 100850, China.
authors.forename: Zhuona
authors.initials: Z
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Drug Metabolism and Pharmacokinetics, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, 27, Taiping Road, Haidian District, Beijing 100850, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drug Metabolism and Pharmacokinetics, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, 27, Taiping Road, Haidian District, Beijing 100850, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Drug Metabolism and Pharmacokinetics, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, 27, Taiping Road, Haidian District, Beijing 100850, China. Electronic address: douguifang@vip.163.com.
authors.forename: Guifang
authors.initials: G
authors.lastname: Dou
authors.affiliation: State Key Laboratory of Drug Metabolism and Pharmacokinetics, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, 27, Taiping Road, Haidian District, Beijing 100850, China. Electronic address: mengzhiyun@vip.163.com.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Meng
mesh_terms: D000631:Aminopyridines / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D001549:Benzamides / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D056572:Histone Deacetylase Inhibitors / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D057230:Limit of Detection; D016014:Linear Models; D009369:Neoplasms / Q000188:drug therapy; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; C547816:N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide
keywords: Benzamide; Chidamide; HPLC–MS/MS; Histone deacetylase inhibitor; Pharmacokinetics