1. HPLC-MS/MS method for quantitative determination of the novel dual inhibitor of FGF and VEGF receptors E-3810 in tumor tissues from xenograft mice and human biopsies
- Author
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Laura Ceriani, Monique Zangarini, Giovanna Damia, Massimo Zucchetti, Ezia Bello, Roberta Cereda, and M. G. Camboni
- Subjects
Detection limit ,medicine.diagnostic_test ,Chemistry ,Fibroblast growth factor receptor 1 ,Analytical chemistry ,Cancer ,Pharmacology ,medicine.disease ,High-performance liquid chromatography ,Matrix (chemical analysis) ,Breast cancer ,Pharmacokinetics ,Biopsy ,medicine ,Spectroscopy - Abstract
We developed and validated a high-performance liquid chromatography–tandem mass spectrometry analytical method to measure E-3810, a novel dual inhibitor of fibroblast growth factor receptor 1 and vascular endothelial growth factor receptor 1–3 in tissues and determined the drug concentration in a biopsy of human breast cancer for the first time. The method is a modification of our previous one in plasma to study the clinical pharmacokinetics of the drug during the phase I/II trial. In view of the changes in matrix, we applied a partial validation protocol to determine recovery, sensitivity, range of linearity, precision, accuracy and stability of the method over three runs in a mouse tumor tissue and liver. The recovery of E-3810 from liver or tumor homogenate was >69%, and the lower limit of quantification was 5 ng/ml. The method was linear in the concentration range 5.0–500.0 ng/ml, as demonstrated by a determination coefficient R2 ≥ 0.9955. The range of the calibration curve was appropriate for the analysis, as demonstrated by the accuracy, which was between 91.4% and 106.7%. Interday precision and accuracy on quality control samples at 9, 30 and 300 ng/ml were 3.1-11.2% and 98.3–111.4%, respectively. The assay was applied successfully to determine the intratumor concentration of E-3810 in different mouse xenograft tumor models and in a biopsy of a patient with breast cancer included in the phase I/II trial of the drug. In mouse tumors, the concentrations of E-3810 were higher than necessary to exert antitumor activity in vitro (1 µM). Even more of interest was the result obtained in a human biopsy of few milligrams, where E-3810 reached 4.9 µg/g (11 µM). Copyright © 2014 John Wiley & Sons, Ltd.
- Published
- 2014