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.
|
Authors | Susan M Christner, Robert A Parise, Erica D Levine, Naiyer A Rizvi, Mrinal M Gounder, Jan H Beumer |
Journal | Journal of pharmaceutical and biomedical analysis
(J Pharm Biomed Anal)
Vol. 100
Pg. 199-204
(Nov 2014)
ISSN: 1873-264X [Electronic] England |
PMID | 25168219
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Validation Study)
|
Copyright | Copyright © 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)
|