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Simultaneous quantification of erlotinib, gefitinib and imatinib in human Titel voorbeeld titel plasma by liquid chromatography tandem mass spectrometry A. Chahbouni, A.J. Wilhelm , J.C.G. den Burger, R.M. Vos, A. Sinjewel. Free University medical center, Department of Clinical Pharmacology and Pharmacy, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands Introduction Results Imatinib (Gleevec®), erlotinib (Terceva®) and gefitinib (Iressa®) are drugs which compete with ATP for binding at the tyrosine kinase receptor. Erlotinib and gefitinib are selective inhibitors of the epidermal growth factor receptor (EGFR), which is often overactive in tumors cells. Erlotinib and gefitinib are common used for treatment of non-small cell lung cancer. Imatinib is an inhibitor of the platet-derived growth factor (PDGF)-receptor and is mainly used by chronic myelogenous leukemia and gastrointestinal stromal tumors. The PDGF (Fig. 1) is one of the growth factors that regulate cell growth and division. Interindividual differences in absorption and metabolism exist and pharmacokinetic interaction with other drugs are described. In case of suspicion of nonadherence, drug–drug interaction, excessive side effects and poor effectiveness, therapeutic drug monitoring (TDM) is useful. The calibration curves in plasma were linear for erlotinib, gefitinib and imatinib over the concentration range of 5-3000; 5-3000 and 5-5000 ng/ml, respectively. The intra- and interday accuracy ranged from 90%-110% and the intra- and interday precision of the method was within 5%. The reported method provided the necessary linearity, precision and accuracy to determine three tyrosine kinase inhibitors in clinical research and for therapeutic drug monitoring. Table 1. Accuracy and precision of the method. Imatinib Erlotinib Gefitinib Intraday Conc. (ng/ml) Av. CV (%) Acc. (%) Conc. Av. (ng/ml) CV (%) Acc. (%) Conc. Av. (ng/ml) CV (%) Acc. (%) 77.4 78.3 1.6 101.2 79.0 80.3 2.7 101.7 84.3 90.2 2.7 107.0 348 347 1.8 99.6 356 364 2.2 102.2 379 417 2.3 110.0 3481 3347 1.8 96.2 2608 2690 1.2 103.1 2782 2994 1.3 107.6 77.4 75.5 1.6 97.6 79.0 77.8 2.2 98.5 84.3 87.1 2.0 103.3 348 338 0.9 97.0 356 361 2.3 101.4 379 402 1.7 106.0 3481 3361 0.6 96.5 2608 2719 3.8 104.2 2782 2894 3.2 104.0 Interday Fig 1. Growth factors, such as PDGF, EGF and FGF. Aim Implementing and developing a method for the simultaneous quantification of imatinib, erlotinib and gefitinib by LC-MS/MS. A simultaneous method for the analysis of these tyrosine kinase inhibitors is more efficient, improves clinical usefulness and makes frequent assaying possible. Method Pre-treatment of the samples was achieved by using liquid-liquid extraction using D-8 imatinib as internal standard. Separation was performed on a Waters® Alliance 2795 LC-system using an XBridge® RP18 column. The mass spectrometer Micromass® was operating in the positive electro spray ionization mode. The analytes were detected by multiple reaction monitoring (MRM), monitoring the transition of the m/z precursor to the m/z of the product ion. Figure 2. shows a representative chromatogram of the tyrosine kinase inhibitors after pre-treatment. Fig 2. Representative chromatogram of internal standard D8-imatinib (A), imatinib (B), gefitinib (C) and erlotinib (D). Av.= average, Acc. = accuracy Applicability of the assay in clinical practise The laboratory of clinical pharmacology and pharmacy participates in the European treatment outcome study (EUTOS) of chronic myelogenous leukaemia initiated by Novartis. The aim of this study is providing the availability of imatinib monitoring on an European level. For this study 15 plasma samples were analyzed, the results of the laboratory of clinical pharmacology and pharmacy (NL01) are described in figure 3. In a study by Picard et al is mentioned that the effectively doses for imatinib a plasma threshold of 1000 ng/ml is considered. Routinely the method is mainly used for TDM of patients which treat with erlotinib. Based on the study of Hidalgo a plasma concentration of 500 ug/L have been estimated to provide a level of EGFR inhibition associated with a relevant degree of antiproliferative activity. Fig. 3. The results of the EUTOS round of standardization. Conclusion: The developed method is sensitive and specific for the simultaneous quantification of erlotinib, gefitinib and imatinib in human plasma by LC-MS/MS. The data confirms that the developed method is robust and has a satisfying accuracy and precision for the quantification of imatinib, erlotinib and gefitinib. This method is suitable for therapeutic drug monitoring and for clinical research. E-mail: [email protected]