Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the determination of the novel proteasome inhibitor CEP-18770 in human plasma and its application in a clinical pharmacokinetic study.

Abstract

CEP-18770, [(1R)-1-{[(2S,3R)-3-hydroxy-2-{[(6-phenyl-2-pyridinyl)carbonyl]amino}butanoyl]amino}-3-methylbutyl]boronic acid, is a novel proteasome inhibitor, now under early clinical evaluation as an anticancer agent. To investigate its clinical pharmacokinetics, a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated to measure the drug in human plasma, based on simple protein precipitation with acetonitrile after the addition of irbesartan as internal standard. The method requires a small volume of sample (100 µl) and is rapid and selective, allowing good resolution of peaks in 5 min. It is sensitive, precise and accurate, with overall precision, expressed as coefficient of variation (CV%), always < 10.0%, accuracy in the range 93.8-107.7% and high recovery, close to 100%. The limit of detection is 0.01 ng/ml and the lower limit of quantitation (LLOQ) is 0.20 ng/ml. The assay was validated in the range from the LLOQ up to 50.00 ng/ml. This is the first method developed and validated for analyzing a proteasome inhibitor with a boronic-acid-based structure in human plasma. The method was successfully applied to study the pharmacokinetics of CEP-18770 in cancer patients with solid tumors or multiple myeloma who had received the drug as a short intravenous bolus during the initial Phase I trial.

• Authors: Federica Sala, Elena Marangon, Renzo Bagnati, Valeria Livi, Roberta Cereda, Maurizio D'Incalci, Massimo Zucchetti
• Journal: Journal of mass spectrometry : JMS (J Mass Spectrom) Vol. 45 Issue 11 Pg. 1299-305 (Nov 2010) ISSN: 1096-9888 [Electronic] England
• PMID: 20872901 (Publication Type: Journal Article)
• Copyright: Copyright © 2010 John Wiley & Sons, Ltd.

Chemical References

• Acetonitriles
• Biphenyl Compounds
• Boronic Acids
• Proteasome Inhibitors
• Tetrazoles
• Threonine
• delanzomib
• Irbesartan
• acetonitrile

Topics

• Acetonitriles (chemistry)
• Biphenyl Compounds (analysis, chemistry)
• Boronic Acids (blood, chemistry, pharmacokinetics)
• Chromatography, High Pressure Liquid (methods)
• Clinical Trials, Phase I as Topic
• Drug Stability
• Humans
• Irbesartan
• Multiple Myeloma
• Neoplasms
• Proteasome Inhibitors
• Reproducibility of Results
• Sensitivity and Specificity
• Tandem Mass Spectrometry (methods)
• Tetrazoles (analysis, chemistry)
• Threonine (analogs & derivatives, blood, chemistry, pharmacokinetics)