A rapid, sensitive, and robust reversed-phase liquid chromatography with tandem mass spectrometry method was developed and validated for the determination of total and unbound ceritinib, a secondgeneration ALK inhibit...A rapid, sensitive, and robust reversed-phase liquid chromatography with tandem mass spectrometry method was developed and validated for the determination of total and unbound ceritinib, a secondgeneration ALK inhibitor, in patient plasma and brain tumor tissue samples. Sample preparation involved simple protein precipitation with acetonitrile. Chromatographic separation was achieved on a Waters ACQUITY UPLC BEH C_(18) column using a 4-min gradient elution consisting of mobile phase A(0.1% formic acid in water) and mobile phase B(0.1% formic acid in acetonitrile), at a flow rate of 0.4 m L/min. Ceritinib and the internal standard([^(13)C_6]ceritinib) were monitored using multiple reaction monitoring mode under positive electrospray ionization. The lower limit of quantitation(LLOQ) was 1 n M of ceritinib in plasma. The calibration curve was linear over ceritinib concentration range of 1–2000 n M in plasma. The intra-and interday precision and accuracy were within the generally accepted criteria for bioanalytical method( o15%).The method was successfully applied to assess ceritinib brain tumor penetration, as assessed by the unbound drug brain concentration to unbound drug plasma concentration ratio, in patients with brain tumors.展开更多
Lung cancer is the major cause of cancer-related mortality, accountingfor over one quarter of cancer deaths. Lung cancers are generally divided into two main categories： SCLC （small cell lung cancer） and NSCLC （no...Lung cancer is the major cause of cancer-related mortality, accountingfor over one quarter of cancer deaths. Lung cancers are generally divided into two main categories： SCLC （small cell lung cancer） and NSCLC （non-small cell lung cancer）. NSCLC accounts for approximately 85% of all lung cancers. ALK （anaplastic largecell kinase） gene rearrangements are identified and targeted resulting in promising response rates for NSCLC in early studies. Ceritinib is a second-generation ALK inhibitor that has demonstrated activity in crizotinib （the first-generation ALK inhibitor）-resistant patients. In this paper, the synthesis, pharmacodynamics, pharmacokinetics, therapeutic trials, adverse events and drug-drug interactions are briefly overviewed in order to make more scholars, medical workers and patients have a more clear and comprehensive recognition on this drug.展开更多
基金supported by the United States Public Health Service Cancer Center Support Grant P30 CA022453Novartis for providing the study drug and isotope-labeled internal standard and providing financial support for the clinical study
文摘A rapid, sensitive, and robust reversed-phase liquid chromatography with tandem mass spectrometry method was developed and validated for the determination of total and unbound ceritinib, a secondgeneration ALK inhibitor, in patient plasma and brain tumor tissue samples. Sample preparation involved simple protein precipitation with acetonitrile. Chromatographic separation was achieved on a Waters ACQUITY UPLC BEH C_(18) column using a 4-min gradient elution consisting of mobile phase A(0.1% formic acid in water) and mobile phase B(0.1% formic acid in acetonitrile), at a flow rate of 0.4 m L/min. Ceritinib and the internal standard([^(13)C_6]ceritinib) were monitored using multiple reaction monitoring mode under positive electrospray ionization. The lower limit of quantitation(LLOQ) was 1 n M of ceritinib in plasma. The calibration curve was linear over ceritinib concentration range of 1–2000 n M in plasma. The intra-and interday precision and accuracy were within the generally accepted criteria for bioanalytical method( o15%).The method was successfully applied to assess ceritinib brain tumor penetration, as assessed by the unbound drug brain concentration to unbound drug plasma concentration ratio, in patients with brain tumors.
文摘Lung cancer is the major cause of cancer-related mortality, accountingfor over one quarter of cancer deaths. Lung cancers are generally divided into two main categories： SCLC （small cell lung cancer） and NSCLC （non-small cell lung cancer）. NSCLC accounts for approximately 85% of all lung cancers. ALK （anaplastic largecell kinase） gene rearrangements are identified and targeted resulting in promising response rates for NSCLC in early studies. Ceritinib is a second-generation ALK inhibitor that has demonstrated activity in crizotinib （the first-generation ALK inhibitor）-resistant patients. In this paper, the synthesis, pharmacodynamics, pharmacokinetics, therapeutic trials, adverse events and drug-drug interactions are briefly overviewed in order to make more scholars, medical workers and patients have a more clear and comprehensive recognition on this drug.
