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Clin Chim Acta. 2017 Jul;470:8-13. doi: 10.1016/j.cca.2017.04.009. Epub 2017 Apr 12.

An UPLC-MS/MS method for the quantification of BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (cobimetinib, trametinib, binimetinib) in human plasma. Application to treated melanoma patients.

Author information

1
Department of Pharmacology, University Hospital Bordeaux, F-33000, France; Univ. Bordeaux INSERM, Bordeaux Population Health Research Center, team PHARMACOEPIDEMIOLOGY, UMR 1219, F-33000 Bordeaux, France. Electronic address: marine.rousset@chu-bordeaux.fr.
2
Department of Pharmacology, University Hospital Bordeaux, F-33000, France.
3
Department of Pharmacology, University Hospital Bordeaux, F-33000, France; Univ. Bordeaux INSERM, Bordeaux Population Health Research Center, team PHARMACOEPIDEMIOLOGY, UMR 1219, F-33000 Bordeaux, France.
4
Department of Dermatology, University Hospital Bordeaux, F-33000, France.
5
Department of Dermatology, University Hospital Bordeaux, F-33000, France; EA2406 Histology and Molecular Pathology of Tumors, University of Bordeaux, F-33000, France.
6
Department of Pharmacology, University Hospital Bordeaux, F-33000, France; Univ. Bordeaux INSERM, Bordeaux Population Health Research Center, team Cancer-environnement-EPICENE, UMR 1219, F-33000 Bordeaux, France.

Abstract

Targeted therapies for cancers are fast-growing therapies. For instance kinase inhibitors such as BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are increasingly used to treat malignant melanoma. The metabolic profile of these drugs can result in great interindividual variability, justifying therapeutic drug monitoring (TDM). We describe a rapid and specific method for quantification of 2 BRAFi (vemurafenib, dabrafenib) and 3 MEKi (cobimetinib, trametinib and binimetinib). Chromatography was performed on a Waters Acquity-UPLC system with CORTECS C18+ column, under a gradient of 10% acetic acid in water/acetonitrile. An Acquity-TQD® with electrospray ionization was used for detection. Samples were prepared by solid phase extraction (Oasis® MCX microElution) before injection in the system. Calibration curves ranges from 0.4 to 100μg/ml for vemurafenib, from 1 to 1000ng/ml for dabrafenib, from 0.5 to 500ng/ml for cobimetinib and binimetinib, and from 0.75 to 250ng/ml for trametinib. At all concentrations the bias was within ±15% of the nominal concentrations and precision was ≤15%. All results were within the acceptance criteria of the EMA guidelines on method validation. This rapid, sensitive and specific UPLC-MS/MS method can perform simultaneous quantification of targeted therapies used in malignant melanoma and is usable for routine TDM.

KEYWORDS:

Dabrafenib; LC-MS/MS; Melanoma; Plasma; Therapeutic drug monitoring; Vemurafenib

PMID:
28412197
DOI:
10.1016/j.cca.2017.04.009
[Indexed for MEDLINE]

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