A novel uHPLC-MS/MS method for the quantitation of AZD7451 (AZ12607092) in human plasma

详细信息    查看全文

• 作者：Cody J. Peer ; Jeffrey L. Brown ; Timothy J. Martin ; Jeffrey Roth ; Shawn D. Spencer ; Patrick Brassil ; Katharine A. McNeill ; Teri N. Kreisl ; Howard A. Fine ; William D. Figg
• 关键词：uHPLC ; ultra-high performance liquid chromatography ; MS ; mass spectrometry ; MS/MS ; tandem mass spectrometry ; QC ; quality control ; LLOQ ; lower limit of quantification
• 刊名：Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences
• 出版年：30 December, 2013
• 年：2013
• 卷：942-943
• 期：Complete
• 页码：107-112
• 全文大小：422 K

文摘

Tropomyosin-related kinases (Trk) are tyrosine kinase receptors implicated in tumor proliferation, invasion, and survival signaling across a number of tumors, making them potentially attractive targets for the treatment of cancer. AZD7451 is a potent and selective inhibitor of Trk kinases currently undergoing a Phase I dose escalation in glioblastoma multiforme at the National Cancer Institute. A key part of early clinical testing for AZD7451 involves demonstrating that pharmacokinetic half-life and clinical exposures of AZD7451 are sufficient to inhibit Trk receptors in preclinical models. To address this need, an ultra sensitive analytical method was developed to measure the AZD7451 profile in human plasma. A liquid-liquid extraction recovered >80% of AZD7451 before quantitative analysis by ultra HPLC-MS/MS. A Varian Polaris^庐 C18-A column and a mass transition of m/z 383.5 鈫?#xA0;340.5 (m/z 389.6 鈫?#xA0;342.0 for the internal standard [²H₆]-AZD7451) was used, and a dynamic calibration range of 0.5-1000 ng/mL was established, which provided a sensitive (<8.5% deviation), and precise (<6%) quantitative assay for AZD7451. AZD7451 demonstrated stability in human plasma at room temperature for 24 h (<7% change) and after extraction at 4 掳C for 24 h (<8% change), and was stable through 4 freeze/thaw cycles (<8% change). This method was used to measure AZD7451 plasma levels in clinical samples to confirm the sensitivity at several time points following AZD7451 treatment in subjects with glioblastoma.