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

Federica Sala, Elena Marangon, Renzo Bagnati, Valeria Livi, Roberta Cereda, Maurizio D'Incalci, Massimo Zucchetti

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1299-1305
Number of pages7
JournalJournal of Mass Spectrometry
Volume45
Issue number11
DOIs
Publication statusPublished - Nov 2010

Keywords

  • CEP-18770
  • HPLC-MS/MS
  • human pharmacokinetics
  • Phase I study
  • proteasome inhibitor

ASJC Scopus subject areas

  • Spectroscopy

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