title: Liquid chromatography-tandem mass spectrometric assay for the multikinase inhibitor regorafenib in plasma.
abstract: Regorafenib has recently been approved for the treatment of colorectal cancer. A bioanalytical liquid chromatography-tandem mass spectrometric assay for this multikinase inhibitor was developed and validated in plasma. The concentration range of the assay was 25-25,000 ng/mL. Protein precipitation with acetonitrile was used as sample pre-treatment with sorafenib as internal standard. The extract was diluted with methanol (25%, v/v) and then injected onto the sub-2 µm particle, bridged ethylsilicia hybrid trifunctional bonded C18 column. Isocratic elution using 0.02% (v/v) formic acid in a methanol-water mixture was used. Compounds were monitored by a triple quadrupole mass spectrometer in the selected reaction monitoring mode after positive electrospray ionization. Double logarithmic calibration was used; within-day precisions, between-day precisions, and accuracies were 3.2-9.2, 4.1-12.3 and 94.8-103.0%, respectively. High drug stability was observed under all relevant storage conditions. The assay was used to measure drug concentrations in a pharmacokinetic study in wild-type FVB mice.
authors.affiliation: Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
authors.forename: Dino
authors.initials: D
authors.lastname: Luethi
authors.forename: Selvi
authors.initials: S
authors.lastname: Durmus
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Sparidans
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods*; D006801:Humans; D016014:Linear Models; D051379:Mice; D010671:Phenylurea Compounds / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D011725:Pyridines / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib
keywords: LC-MS/MS; bioanalytical assay; multikinase inhibitor; regorafenib