A rugged and accurate liquid chromatography-tandem mass spectrometry method for the determination of asunaprevir, an NS3 protease inhibitor, in plasma

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• 作者：Long Yuan^a ; Hao Jiang^a ; Zheng Ouyang^b ; Yuan-Qing Xia^b ; ¹ ; Jianing Zeng^a ; ^{jianing.zeng@bms.com} ; Qianping Peng^c ; Robert W. Lange^d ; Yuzhong Deng^a ; ² ; Mark E. Arnold^a ; Anne-Franç ; oise Aubry^a
• 关键词：Asunaprevir ; BMS-650032 ; Hepatitis C virus (HCV) ; Quantitative ; LC&ndash ; MS/MS
• 刊名：Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences
• 出版年：2013
• 出版时间：15 March, 2013
• 年：2013
• 卷：921-922
• 期：Complete
• 页码：81-86
• 全文大小：814 K

文摘

Asunaprevir (BMS-650032) is a potent hepatitis C virus (HCV) non-structural protein protease inhibitor currently in Phase III clinical trials for the treatment of HCV infection. A rugged and accurate LC-MS/MS method was developed and validated for the quantitation of asunaprevir in rat, dog, monkey, rabbit and mouse plasma. A systematic method screening and optimization strategy was applied to achieve optimized mass spectrometry, chromatography, and sample extraction conditions. The validated method utilized stable-isotope labeled D₉-asunaprevir as the internal standard. The samples were extracted by liquid-liquid extraction using 10 % ethyl acetate in hexane. Chromatographic separation was achieved with gradient elution on a Waters Atlantis dC18 analytical column. Analyte and its internal standard were detected by positive ion electrospray tandem mass spectrometry. The standard curve, which ranged from 5.00 to 2000 ng/mL for asunaprevir, was fitted to a 1/x² weighted linear regression model. The intra-assay precision was within ¡À3.6 % CV, inter-assay precision was within ¡À4.0 % CV, and the assay accuracy was within ¡À8.1 % of the nominal values in all the species. The method was successfully applied to support multiple pre-clinical toxicokinetic studies in different species.