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Quantitative method for the determination of iso-fludelone (KOS-1803) in human plasma by LC-MS/MS.

Abstract
Epothilones are relatively new tubulin-poison anticancer drugs. Iso-fludelone (KOS-1803) is a synthetic third generation epothilone drug discovered at Memorial Sloan Kettering Cancer Center, and currently in phase I clinical trials. We report an LC-MS/MS assay for the sensitive, accurate and precise quantitation of iso-fludelone in 0.2mL of human plasma. Validation was performed according to FDA guidance. The assay comprised of KOS-1724 as the internal standard and an MTBE liquid-liquid extraction with a water wash step. Separation was achieved with an YMC-Pack ODS-AQ column and an isocratic mobile phase of 0.1% formic acid in acetonitrile and water (70:30, v/v) at 0.3mL/min for 4min. Chromatographic separation was followed by electrospray, positive-mode ionization tandem mass spectrometric detection in the multiple reaction monitoring (MRM) mode. The assay was linear from 0.1 to 300ng/mL and was accurate (-9.41 to -7.07%) and precise (1.03-13.7%) which fulfilled FDA criteria for validation. Recovery from plasma was 73.9-79.7% and ion suppression was negligible (-22.8 to -31.3%). Plasma freeze-thaw stability (99.97-105.7%), stability for 11 months at -80°C (94.93-107.9%), and stability for 6h at room temperature (94.75-105.5%) were all acceptable. This assay is currently being applied to quantitate iso-fludelone in clinical samples.
AuthorsSusan M Christner, Robert A Parise, Erica D Levine, Naiyer A Rizvi, Mrinal M Gounder, Jan H Beumer
JournalJournal of pharmaceutical and biomedical analysis (J Pharm Biomed Anal) Vol. 100 Pg. 199-204 (Nov 2014) ISSN: 1873-264X [Electronic] England
PMID25168219 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Validation Study)
CopyrightCopyright © 2014 Elsevier B.V. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Epothilones
  • Tubulin Modulators
  • fludelone
Topics
  • Antineoplastic Agents (blood)
  • Calibration
  • Chromatography, Liquid (standards)
  • Cold Temperature
  • Drug Stability
  • Epothilones (blood)
  • Humans
  • Liquid-Liquid Extraction
  • Reference Standards
  • Reproducibility of Results
  • Spectrometry, Mass, Electrospray Ionization (standards)
  • Tandem Mass Spectrometry (standards)
  • Time Factors
  • Tubulin Modulators (blood)

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