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 journalArticle

9 Citations (Scopus)

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

Fingerprint

Boronic Acids
Plasma (human)
Proteasome Inhibitors
Pharmacokinetics
irbesartan
liquid chromatography
High performance liquid chromatography
Tandem Mass Spectrometry
inhibitors
Mass spectrometry
mass spectroscopy
High Pressure Liquid Chromatography
Acids
drugs
Acetonitrile
Pharmaceutical Preparations
Antineoplastic Agents
Tumors
Assays
acids

Keywords

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

ASJC Scopus subject areas

  • Spectroscopy

Cite this

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title = "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.",
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T1 - 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

AU - Sala, Federica

AU - Marangon, Elena

AU - Bagnati, Renzo

AU - Livi, Valeria

AU - Cereda, Roberta

AU - D'Incalci, Maurizio

AU - Zucchetti, Massimo

PY - 2010/11

Y1 - 2010/11

N2 - 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.

AB - 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.

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