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Simultaneous determination of a novel c-Met/AXL dual-target small-molecule inhibitor BPI-9016M and its metabolites in human plasma by liquid chromatography-tandem mass spectrometry: Application in a pharmacokinetic study in Chinese advanced solid tumor patients.

Abstract

BPI-9016M is a novel dual-target small-molecule inhibitor targeting c-Met and AXL, which was developed by Betta Pharmaceuticals Co., Ltd (Hangzhou, China). It has great potential in the treatment of advanced cancer. A high throughput quantitation method, based on liquid chromatography-tandem mass spectrometry, was developed and validated for the simultaneous determination of BPI-9016M and its main metabolite, M1 and M2-2, in human plasma with a sample preparation method of precipitation of protein. Liquid chromatographic separation was performed with a gradient elution of formic acid-10mM ammonium acetate aqueous solution (1:1000, v/v) and acetonitrile at a flow rate of 0.4mL/min within 2.2min. A Waters ACQUITY UPLC BEH C18 column (1.7μm, 2.1×50mm) was chosen, of which the temperature was set to be 40°C. Mass spectrometric detection, which were achieved in positive mode, were performed by multiple reaction monitoring with SCIEX API 5500 Qtrap equipped with an ESI ion source. This method showed good linearity, accuracy and precision in the range of 0.4-200ng/mL for BPI-9016M and 0.8-800ng/mL for M1 and M2-2, with high recovery and slight matrix effect for all analytes. And under the conditions same as stability assessments in method validation, the three analytes stayed stable during the entire destiny of a clinical sample from the collection of whole blood to the analysis of plasma by this method. The validated method was successfully applied to a first-in-human, dose-escalation phase I clinical trial in Chinese advanced solid tumor patients for the pharmacokinetic research of BPI-9016M tablet after oral administration. The concentration-time curves of BPI-9016M, M1, M2-2 were detailly captured with good veracity. And according to the results of hemolysis assessment, plasma concentrations of analytes in hemolyzed plasma samples could be reported normally without label.

Authors+Show Affiliations

Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 41. Damucang Hutong, Xicheng District, Beijing, 100032, China. Electronic address: cncuixinge@163.com.Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 41. Damucang Hutong, Xicheng District, Beijing, 100032, China. Electronic address: zhengxin1@pumch.cn.Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 41. Damucang Hutong, Xicheng District, Beijing, 100032, China. Electronic address: 13601169983@139.com.Betta Pharmaceuticals Co., Ltd, No. 589 Hongfeng Road, Yuhang Economic and Technological Development Area, Hangzhou, China. Electronic address: fenlai.tan@bettapharma.com.Betta Pharmaceuticals Co., Ltd, No. 589 Hongfeng Road, Yuhang Economic and Technological Development Area, Hangzhou, China. Electronic address: lieming.ding@bettapharma.com.Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 41. Damucang Hutong, Xicheng District, Beijing, 100032, China. Electronic address: pei.hu.pumch@gmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29028616

Citation

Cui, Xinge, et al. "Simultaneous Determination of a Novel c-Met/AXL Dual-target Small-molecule Inhibitor BPI-9016M and Its Metabolites in Human Plasma By Liquid Chromatography-tandem Mass Spectrometry: Application in a Pharmacokinetic Study in Chinese Advanced Solid Tumor Patients." Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, vol. 1068-1069, 2017, pp. 33-40.
Cui X, Zheng X, Jiang J, et al. Simultaneous determination of a novel c-Met/AXL dual-target small-molecule inhibitor BPI-9016M and its metabolites in human plasma by liquid chromatography-tandem mass spectrometry: Application in a pharmacokinetic study in Chinese advanced solid tumor patients. J Chromatogr B Analyt Technol Biomed Life Sci. 2017;1068-1069:33-40.
Cui, X., Zheng, X., Jiang, J., Tan, F., Ding, L., & Hu, P. (2017). Simultaneous determination of a novel c-Met/AXL dual-target small-molecule inhibitor BPI-9016M and its metabolites in human plasma by liquid chromatography-tandem mass spectrometry: Application in a pharmacokinetic study in Chinese advanced solid tumor patients. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 1068-1069, pp. 33-40. doi:10.1016/j.jchromb.2017.10.017.
Cui X, et al. Simultaneous Determination of a Novel c-Met/AXL Dual-target Small-molecule Inhibitor BPI-9016M and Its Metabolites in Human Plasma By Liquid Chromatography-tandem Mass Spectrometry: Application in a Pharmacokinetic Study in Chinese Advanced Solid Tumor Patients. J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Nov 15;1068-1069:33-40. PubMed PMID: 29028616.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Simultaneous determination of a novel c-Met/AXL dual-target small-molecule inhibitor BPI-9016M and its metabolites in human plasma by liquid chromatography-tandem mass spectrometry: Application in a pharmacokinetic study in Chinese advanced solid tumor patients. AU - Cui,Xinge, AU - Zheng,Xin, AU - Jiang,Ji, AU - Tan,Fenlai, AU - Ding,Lieming, AU - Hu,Pei, Y1 - 2017/10/08/ PY - 2017/07/18/received PY - 2017/09/14/revised PY - 2017/10/07/accepted PY - 2017/10/14/pubmed PY - 2017/12/5/medline PY - 2017/10/14/entrez KW - Advanced solid tumor KW - BPI-9016M KW - Chinese KW - Human plasma KW - LC-MS/MS KW - c-Met/AXL dual-target inhibitor SP - 33 EP - 40 JF - Journal of chromatography. B, Analytical technologies in the biomedical and life sciences JO - J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. VL - 1068-1069 N2 - BPI-9016M is a novel dual-target small-molecule inhibitor targeting c-Met and AXL, which was developed by Betta Pharmaceuticals Co., Ltd (Hangzhou, China). It has great potential in the treatment of advanced cancer. A high throughput quantitation method, based on liquid chromatography-tandem mass spectrometry, was developed and validated for the simultaneous determination of BPI-9016M and its main metabolite, M1 and M2-2, in human plasma with a sample preparation method of precipitation of protein. Liquid chromatographic separation was performed with a gradient elution of formic acid-10mM ammonium acetate aqueous solution (1:1000, v/v) and acetonitrile at a flow rate of 0.4mL/min within 2.2min. A Waters ACQUITY UPLC BEH C18 column (1.7μm, 2.1×50mm) was chosen, of which the temperature was set to be 40°C. Mass spectrometric detection, which were achieved in positive mode, were performed by multiple reaction monitoring with SCIEX API 5500 Qtrap equipped with an ESI ion source. This method showed good linearity, accuracy and precision in the range of 0.4-200ng/mL for BPI-9016M and 0.8-800ng/mL for M1 and M2-2, with high recovery and slight matrix effect for all analytes. And under the conditions same as stability assessments in method validation, the three analytes stayed stable during the entire destiny of a clinical sample from the collection of whole blood to the analysis of plasma by this method. The validated method was successfully applied to a first-in-human, dose-escalation phase I clinical trial in Chinese advanced solid tumor patients for the pharmacokinetic research of BPI-9016M tablet after oral administration. The concentration-time curves of BPI-9016M, M1, M2-2 were detailly captured with good veracity. And according to the results of hemolysis assessment, plasma concentrations of analytes in hemolyzed plasma samples could be reported normally without label. SN - 1873-376X UR - https://www.unboundmedicine.com/medline/citation/29028616/Simultaneous_determination_of_a_novel_c_Met/AXL_dual_target_small_molecule_inhibitor_BPI_9016M_and_its_metabolites_in_human_plasma_by_liquid_chromatography_tandem_mass_spectrometry:_Application_in_a_pharmacokinetic_study_in_Chinese_advanced_solid_tumor_patients_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1570-0232(17)31230-8 DB - PRIME DP - Unbound Medicine ER -