Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the determination of the novel inhibitor of angiogenesis E-3810 in human plasma and its application in a clinical pharmacokinetic study

Federica Sala, Renzo Bagnati, Valeria Livi, Roberta Cereda, Maurizio D'Incalci, Massimo Zucchetti

Research output: Contribution to journalArticle

Abstract

E-3810, 6-[[7-[(1-aminocyclopropyl)methoxy]-6-methoxy-4-quinolyl]oxy]-N- methyl-naphthalene-1-carboxamide, is a novel, potent, dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors with antiangiogenic properties, now under early clinical evaluation as an anticancer agent. To investigate its clinical pharmacokinetics, a high-performance liquid chromatography-tandem mass spectrometry method was developed and validated to measure the drug in human plasma on the basis of simple protein precipitation with methanol after addition of deuterated E-3810 as internal standard. The method requires a small volume of sample (100 μl) and is rapid and selective, allowing good resolution of peaks in 5 min. It is sensitive, precise, and accurate, with overall precision, expressed as CV%, always ≤7.1%, accuracy in the range 92.7%-104.4%, and high recovery, close to 100%. The limit of detection is 0.01ng/ml, and the lower limit of quantitation is 2.0ng/ml. The assay was validated in the range from the lower limit of quantitation up to 500.0ng/ml. This is the first method developed and validated for analyzing E-3810 in human plasma. The method has been successfully applied to study E-3810 pharmacokinetics in cancer patients with solid tumors who are receiving daily oral doses of the drug during the phase I trial.

Original languageEnglish
Pages (from-to)1039-1045
Number of pages7
JournalJournal of Mass Spectrometry
Volume46
Issue number10
DOIs
Publication statusPublished - Oct 2011

Keywords

  • E-3810
  • FGFR/VEGFR inhibitor
  • HPLC-MS/MS
  • pharmacokinetics
  • phase I study

ASJC Scopus subject areas

  • Spectroscopy

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