title: Determination of cobimetinib in human plasma using protein precipitation extraction and high-performance liquid chromatography coupled to mass spectrometry.
abstract: Inhibition of MAP/ERK kinase (MEK) is a promising strategy to control the growth of tumors that are dependent on aberrant signaling in the MEK pathway. Cobimetinib (GDC-0973) (S)-[3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-((S)-3-hydroxy-3-piperidin-2-yl-azetidin-1-yl)-methanone) inhibits proliferation of a variety of human tumor cell lines by inhibiting MEK1 and MEK2. A specific high performance liquid chromatography-mass spectrometric assay was developed and validated for the determination of cobimetinib in human plasma. The overall mean recovery using protein precipitation extraction with acetonitrile was found to be 54.1%. The calibration curve was ranged from 0.20 to 100ng/mL. The LLOQ was sensitive enough to detect terminal phase concentrations of the drug. The intra- and inter-assay precision (%CV) was within 10.3% and 9.5% for cobimetinib. The assay accuracy (%RE) was within ±13.7% of the nominal concentration values for cobimetinib with the normal analytical QCs. The developed assay was successfully used to analyze the human plasma samples (for pharmacokinetic analysis) from clinical trials.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA 94080, United States. Electronic address: yuzhongd@gene.com.
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Clinical Pharmacology, Genentech, South San Francisco, CA 94080, United States.
authors.forename: Luna
authors.initials: L
authors.lastname: Musib
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA 94080, United States.
authors.forename: Edna
authors.initials: E
authors.lastname: Choo
authors.affiliation: Quintiles BioSciences, Ithaca, NY 14850, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Chapple
authors.affiliation: Quintiles BioSciences, Ithaca, NY 14850, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Burke
authors.affiliation: Quintiles BioSciences, Ithaca, NY 14850, United States.
authors.forename: James
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Clinical Pharmacology, Genentech, South San Francisco, CA 94080, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Eppler
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA 94080, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Dean
mesh_terms: D001384:Azetidines / Q000097:blood* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D018592:Cross-Over Studies; D006801:Humans; D057230:Limit of Detection; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D013058:Mass Spectrometry / Q000379:methods*; D010880:Piperidines / Q000097:blood* / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics; D011506:Proteins / Q000737:chemistry*; D015203:Reproducibility of Results
chemical_list: D001384:Azetidines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011506:Proteins; D048369:MAP Kinase Kinase 1; C574276:cobimetinib
keywords: Cobimetinib; GDC-0973; LC–MS/MS; Validation