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.
authors.affiliation: Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Sala
authors.forename: Elena
authors.initials: E
authors.lastname: Marangon
authors.forename: Renzo
authors.initials: R
authors.lastname: Bagnati
authors.forename: Valeria
authors.initials: V
authors.lastname: Livi
authors.forename: Roberta
authors.initials: R
authors.lastname: Cereda
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Massimo
authors.initials: M
authors.lastname: Zucchetti
mesh_terms: D000097:Acetonitriles / Q000737:chemistry; D001713:Biphenyl Compounds / Q000032:analysis / Q000737:chemistry; D001897:Boronic Acids / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D017321:Clinical Trials, Phase I as Topic; D004355:Drug Stability; D006801:Humans; D000077405:Irbesartan; D009101:Multiple Myeloma; D009369:Neoplasms; D061988:Proteasome Inhibitors; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*; D013777:Tetrazoles / Q000032:analysis / Q000737:chemistry; D013912:Threonine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000097:Acetonitriles; D001713:Biphenyl Compounds; D001897:Boronic Acids; D061988:Proteasome Inhibitors; D013777:Tetrazoles; D013912:Threonine; C527966:delanzomib; D000077405:Irbesartan; C032159:acetonitrile