Development and validation of LC–MS/MS assays for the quantification of E7080 and metabolites in various human biological matrices
2012
Dubbelman, A.C. | Rosing, H. | Thijssen, B. | Gebretensae, A. | Lucas, L. | Chen, H. | Shumaker, R. | Schellens, J.H.M. | Beijnen, J.H.
To support clinical pharmacokinetic studies with the anticancer agent E7080 (lenvatinib), liquid chromatography tandem mass spectrometry (LC–MS/MS) methods were developed for the quantification of E7080 and four of its metabolites in human plasma, urine and faeces and of E7080 in whole blood. Cross-analyte interferences between metabolites and parent compound were expected and therefore accounted for early in the method development. Plasma, urine and faeces samples were extracted with acetonitrile. Chromatographic separation was achieved on a 50mm×2.1mm I.D. XTerra MS C18 column, with a 0.2mL/min flow and gradient elution starting with 100% formic acid in water, followed by an increasing percentage of acetonitrile. Whole blood samples were extracted with diethyl ether and extracts were injected on a 150mm×2.1mm I.D. Symmetry Shield RP8 column. Detection was performed using an API3000 triple quadrupole mass spectrometer, with a turbo ion spray interface, operating in positive ion mode. Using 250μL of plasma, E7080 and its metabolites could be quantified between 0.25 and 50.0ng/mL. The quantifiable ranges of E7080 in whole blood, urine and faeces were 0.25–500ng/mL, 1.00–500ng/mL and 0.1–25μg/g, using sample volumes of 250μL, 200μL and 250mg, respectively. Calibration curves in all matrices were linear with a correlation coefficient (r²) of 0.994 or better. At the lower limit of quantification, accuracies were within ±20% of the nominal concentration with CV values less than 20%. At the other concentrations the accuracies were within ±15% of the nominal concentration with CV values below 15%. The developed methods have successfully been applied in a mass balance study of E7080.
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