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.
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 0.01 ng/ml, and the lower limit of quantitation is 2.0 ng/ml. The assay was validated in the range from the lower limit of quantitation up to 500.0 ng/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.
Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Federica
F
Sala
Renzo
R
Bagnati
Valeria
V
Livi
Roberta
R
Cereda
Maurizio
M
D'Incalci
Massimo
M
Zucchetti
D020533:Angiogenesis Inhibitors / Q000097:blood*; D002138:Calibration; D002851:Chromatography, High Pressure Liquid / Q000191:economics / Q000379:methods; D006801:Humans; D057230:Limit of Detection; D009281:Naphthalenes / Q000097:blood*; D009369:Neoplasms / Q000097:blood; D011804:Quinolines / Q000097:blood*; D064750:Rabeprazole; D053719:Tandem Mass Spectrometry / Q000191:economics / Q000379:methods*
D020533:Angiogenesis Inhibitors; D009281:Naphthalenes; D011804:Quinolines; D064750:Rabeprazole