title: A LC/MS/MS micro-method for human plasma quantification of vemurafenib. Application to treated melanoma patients.
abstract: 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.
authors.affiliation: Laboratoire de Pharmacologie - Toxicologie, Centre Hospitalier Universitaire Raymond Poincaré, AP-HP, 104 Boulevard R. Poincaré, 92380 Garches et Université Versailles Saint-Quentin, France. Electronic address: jean-claude.alvarez@rpc.aphp.fr.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Alvarez
authors.affiliation: Service de dermatologie, Centre Hospitalier Universitaire Ambroise Paré, AP-HP, 9 Avenue Charles de Gaulle, 92104 Boulogne-Billancourt et Université Versailles Saint-Quentin, France.
authors.forename: Elisa
authors.initials: E
authors.lastname: Funck-Brentano
authors.affiliation: Laboratoire de Pharmacologie - Toxicologie, Centre Hospitalier Universitaire Raymond Poincaré, AP-HP, 104 Boulevard R. Poincaré, 92380 Garches et Université Versailles Saint-Quentin, France.
authors.forename: Emuri
authors.initials: E
authors.lastname: Abe
authors.affiliation: Laboratoire de Pharmacologie - Toxicologie, Centre Hospitalier Universitaire Raymond Poincaré, AP-HP, 104 Boulevard R. Poincaré, 92380 Garches et Université Versailles Saint-Quentin, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Etting
authors.affiliation: Service de dermatologie, Centre Hospitalier Universitaire Ambroise Paré, AP-HP, 9 Avenue Charles de Gaulle, 92104 Boulogne-Billancourt et Université Versailles Saint-Quentin, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Saiag
authors.affiliation: Laboratoire de Pharmacologie - Toxicologie, Centre Hospitalier Universitaire Raymond Poincaré, AP-HP, 104 Boulevard R. Poincaré, 92380 Garches et Université Versailles Saint-Quentin, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Knapp
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000097:blood* / Q000627:therapeutic use; D002853:Chromatography, Liquid / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D007211:Indoles / Q000097:blood* / Q000627:therapeutic use*; D057230:Limit of Detection; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D013449:Sulfonamides / Q000097:blood* / Q000627:therapeutic use*; D053719:Tandem Mass Spectrometry / Q000379:methods*; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib
keywords: LC–MS/MS; Melanoma; Pharmacokinetic; Plasma; Vemurafenib