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 language | English |
|---|---|
| Pages (from-to) | 1299-1305 |
| Number of pages | 7 |
| Journal | Journal of Mass Spectrometry |
| Volume | 45 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 2010 |
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Keywords
- CEP-18770
- HPLC-MS/MS
- human pharmacokinetics
- Phase I study
- proteasome inhibitor
ASJC Scopus subject areas
- Spectroscopy
Cite this
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. / Sala, Federica; Marangon, Elena; Bagnati, Renzo; Livi, Valeria; Cereda, Roberta; D'Incalci, Maurizio; Zucchetti, Massimo.
In: Journal of Mass Spectrometry, Vol. 45, No. 11, 11.2010, p. 1299-1305.Research output: Contribution to journal › Article
}
TY - JOUR
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.
KW - CEP-18770
KW - HPLC-MS/MS
KW - human pharmacokinetics
KW - Phase I study
KW - proteasome inhibitor
UR - http://www.scopus.com/inward/record.url?scp=78649593066&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78649593066&partnerID=8YFLogxK
U2 - 10.1002/jms.1842
DO - 10.1002/jms.1842
M3 - Article
C2 - 20872901
AN - SCOPUS:78649593066
VL - 45
SP - 1299
EP - 1305
JO - Biomedical Mass Spectrometry
JF - Biomedical Mass Spectrometry
SN - 1076-5174
IS - 11
ER -