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Title

Quantification of the next-generation oral anti-tumor drugs dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib and two metabolites in human plasma by liquid chromatography-tandem mass spectrometry

Authors
Mercier, Thomas
Wagner, Anna Dorothea
Michielin, Olivier
Ellefsen-Lavoie, Kim
Cagnon, Laurène
Diezi, Manuel
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Published in Journal of Chromatography. B. 2018, vol. 1083, p. 124-136
Abstract A sensitive and selective method of high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS) has been developed for the simultaneous quantification of six anticancer protein kinase inhibitors (PKIs), dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib, and two active metabolites (regorafenib-M2 and regorafenib-M5) in human plasma. Plasma protein precipitation with methanol enables the sample extraction of 100 μL aliquot of plasma. Analytes are detected by electrospray triple-stage quadrupole mass spectrometry and quantified using the calibration curves with stable isotope-labeled internal standards. The method was validated based on FDA recommendations, including assessment of extraction yield (74-104%), matrix effects, analytical recovery (94-104%) with low variability (<15%). The method is sensitive (lower limits of quantification within 1 to 200 ng/mL), accurate (intra- and inter-assay bias: -0.3% to +12.7%, and -3.2% to +6.3%, respectively) and precise (intra- and inter-assay CVs within 0.7-7.3% and 2.5-8.0%, respectively) over the clinically relevant concentration range (upper limits of quantification 500 to 100,000 ng/mL). This method is applied in our laboratory for both clinical research programs and routine therapeutic drug monitoring service of PKIs.
Keywords Administration, OralAntineoplastic Agents/administration & dosage/blood/chemistry/pharmacokineticsAzetidines/administration & dosage/blood/chemistry/pharmacokineticsChildChromatography, High Pressure Liquid/methodsHumansImidazoles/administration & dosage/blood/chemistry/pharmacokineticsIndoles/administration & dosage/blood/chemistry/pharmacokineticsLimit of DetectionLinear ModelsOximes/administration & dosage/blood/chemistry/pharmacokineticsPhenylurea Compounds/administration & dosage/blood/chemistry/pharmacokineticsPiperidines/administration & dosage/blood/chemistry/pharmacokineticsPyridines/administration & dosage/blood/chemistry/pharmacokineticsPyridones/administration & dosage/blood/chemistry/pharmacokineticsPyrimidines/administration & dosage/blood/chemistry/pharmacokineticsPyrimidinones/administration & dosage/blood/chemistry/pharmacokineticsReproducibility of ResultsSulfonamides/administration & dosage/blood/chemistry/pharmacokineticsTandem Mass Spectrometry/methodsVemurafenib
Identifiers
PMID: 29544202
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Research group Pharmacie hospitalière et clinique
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CARDOSO, Evelina et al. Quantification of the next-generation oral anti-tumor drugs dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib and two metabolites in human plasma by liquid chromatography-tandem mass spectrometry. In: Journal of Chromatography. B, 2018, vol. 1083, p. 124-136. doi: 10.1016/j.jchromb.2018.02.008 https://archive-ouverte.unige.ch/unige:138479

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Deposited on : 2020-07-17

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