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

4 Citations (Scopus)

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

Fingerprint

Plasma (human)
angiogenesis
Angiogenesis Inhibitors
Pharmacokinetics
liquid chromatography
High performance liquid chromatography
Tandem Mass Spectrometry
inhibitors
Mass spectrometry
mass spectroscopy
High Pressure Liquid Chromatography
drugs
Fibroblasts
Naphthalene
Tumors
Assays
Methanol
fibroblasts
Proteins
naphthalene

Keywords

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

ASJC Scopus subject areas

  • Spectroscopy

Cite this

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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.",
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AU - Bagnati, Renzo

AU - Livi, Valeria

AU - Cereda, Roberta

AU - D'Incalci, Maurizio

AU - Zucchetti, Massimo

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