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

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

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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® C18-A column and a mass transition of m/z 383.5→340.5 (m/z 389.6→342.0 for the internal standard [2H6]-AZD7451) was used, and a dynamic calibration range of 0.5-1000ng/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 24h (<7% change) and after extraction at 4°C for 24h (<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.

Original languageEnglish (US)
Pages (from-to)107-112
Number of pages6
JournalJournal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Volume942-943
DOIs
StatePublished - Dec 30 2013
Externally publishedYes

Keywords

  • Tandem mass spectrometry
  • Tropomyosin-related kinase
  • Ultra-high performance liquid chromatography

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Clinical Biochemistry
  • Cell Biology

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