As previously shown for imatinib, therapeutic drug monitoring (TDM) of vemurafenib should be important to measure efficacy of the treatment in melanoma patient. A micro-method based on liquid chromatography coupled to triple quadrupole spectrometry detection using only 10μL of plasma was validated. A simple protein precipitation with water/acetonitrile was used after addition of vemurafenib-(13)C6 as internal standard. The ion transitions used to monitor analytes were m/z 490.2→m/z 255.2 and m/z 383.3 for vemurafenib and m/z 496.2→m/z 261.2 and m/z 389.3 for vemurafenib-(13)C6. Calibration curves were linear in the 0.1-100μg/mL range, the limits of detection and quantification being 0.01μg/mL and 0.1μg/mL, respectively. The intra- and inter-assay precisions evaluated at 0.1, 0.3, 15, 45 and 80μg/mL were lower than 13.3% and the accuracies were in the 93.7-105.8 range. No matrix effect was observed. At steady state, the results of TDM of vemurafenib in 26 patients treated by 960mg twice daily (n=60 samples), 13 patients with 740mg twice daily (n=13) and one with 1200mg twice daily (n=3) showed a great variability of the pharmacokinetics of this compound.
Keywords: LC–MS/MS; Melanoma; Pharmacokinetic; Plasma; Vemurafenib.
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