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J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Apr 15;1083:124-136. doi: 10.1016/j.jchromb.2018.02.008. Epub 2018 Feb 8.

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.

Author information

1
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
2
Laboratory of the Service of Clinical Pharmacology, Department of Laboratories, Lausanne University Hospital, Lausanne, Switzerland.
3
Service of Medical Oncology, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.
4
Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.
5
Paediatric Hemato-Oncology Unit, Department of Paediatrics, Lausanne University Hospital, Lausanne, Switzerland.
6
Service of Clinical Pharmacology, Department of Laboratories, Lausanne University Hospital, Lausanne, Switzerland.
7
Service of Clinical Pharmacology, Department of Laboratories, Lausanne University Hospital, Lausanne, Switzerland; Pharmacy of Eastern Vaud Hospitals, Vevey, Switzerland.
8
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland; Service of Clinical Pharmacology, Department of Laboratories, Lausanne University Hospital, Lausanne, Switzerland.
9
Laboratory of the Service of Clinical Pharmacology, Department of Laboratories, Lausanne University Hospital, Lausanne, Switzerland. Electronic address: LaurentArthur.Decosterd@chuv.ch.

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:

Drug monitoring; LC-MS/MS; Targeted anticancer therapy; Tyrosine kinase inhibitor

PMID:
29544202
DOI:
10.1016/j.jchromb.2018.02.008
[Indexed for MEDLINE]

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