A rapid, accurate and robust UHPLC-MS/MS method for quantitative determination of BMS-927711, a CGRP receptor antagonist, in plasma in support of non-clinical toxicokinetic studies

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• 作者：Naiyu Zheng ; Jianing Zeng ; Billy Akinsanya ; Adela Buzescu ; Yuan-Qing Xia ; Van Ly ; Kevin Trouba ; Qianping Peng ; Anne-Fran?oise Aubry ; Mark E. Arnold
• 关键词：BMS-927711 ; CGRP antagonist ; Quantitation ; UHPLC&ndash ; MS/MS ; N-carbamoyl glucuronide ; Stability
• 刊名：Journal of Pharmaceutical and Biomedical Analysis
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：83
• 期：Complete
• 页码：237-248
• 全文大小：747 K

文摘

BMS-927711 is a calcitonin gene-related peptide (CGRP) receptor antagonist that is being developed for the treatment of migraine. A rapid, accurate and robust assay was developed and validated for the quantitation of BMS-927711 in rat, monkey, rabbit and mouse plasma using ultra high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS). A simplified method screening strategy was utilized that included a liquid-liquid extraction (LLE) methodology and eleven LC columns (ten sub-2 ¦Ìm UHPLC columns and one 2.6 ¦Ìm HPLC column) for screening with emphasis on the removal of phospholipids, avoidance of metabolite interference and ruggedness of LC conditions. A stable isotope labeled [¹³C₂, D₄]-BMS-927711 was used as the internal standard, and 50 ¦ÌL of plasma samples were used for extraction by automated LLE with methyl tert-butyl ether (MTBE) in 96-well format. Chromatographic separation was achieved with an isocratic elution and a gradient column wash on a Waters Acuity UPLC^? BEH C18 column (2.1 mm ¡Á 50 mm, 1.7 ¦Ìm) with run time of 3.7 min. Positive electrospray ionization was performed using selected reaction monitoring (SRM) with transitions of m/z 535 > 256 for BMS-927711 and m/z 541 > 256 for [¹³C₂, D₄]-BMS-927711. The standard curve, which ranged from 3.00 to 3000 ng/mL for BMS-927711, was fitted to a 1/x² weighted linear regression model. The intra-assay precision was within 5.2 % CV, inter-assay precision was within 5.9 % CV, and the assay accuracy was within ¡À5.2 % deviation ( % Dev) of the nominal values in all the species. The stability of an N-carbamoyl glucuronide metabolite was carefully investigated, and the conversion of this metabolite to BMS-927711 was minimal and manageable without a stabilization procedure. The method was successfully applied to multiple non-clinical toxicokinetic studies in different species in support of the investigative new drug (IND) filing.