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.
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Authors | Yuzhong Deng, Luna Musib, Edna Choo, Matthew Chapple, Sarah Burke, James Johnson, Steve Eppler, Brian Dean |
Journal | Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
(J Chromatogr B Analyt Technol Biomed Life Sci)
Vol. 972
Pg. 117-23
(Dec 01 2014)
ISSN: 1873-376X [Electronic] Netherlands |
PMID | 25444546
(Publication Type: Journal Article, Randomized Controlled Trial)
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Copyright | Copyright © 2014 Elsevier B.V. All rights reserved. |
Chemical References |
- Azetidines
- Piperidines
- Protein Kinase Inhibitors
- Proteins
- MAP Kinase Kinase 1
- cobimetinib
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Topics |
- Azetidines
(blood, pharmacokinetics)
- Cell Line, Tumor
- Chromatography, High Pressure Liquid
(methods)
- Cross-Over Studies
- Humans
- Limit of Detection
- MAP Kinase Kinase 1
(antagonists & inhibitors)
- Mass Spectrometry
(methods)
- Piperidines
(blood, pharmacokinetics)
- Protein Kinase Inhibitors
(blood, pharmacokinetics)
- Proteins
(chemistry)
- Reproducibility of Results
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