Abstract
Imatinib (Gleevec® or Glivec®) is a competitive inhibitor of protein tyrosine kinase is currently used for the treatment of chronic myeloid leukaemia (CML), Philadelphia chromosome-positive acute lymphoblatique leukemia and for other malignant pathologies.
Although there is no clearly defined therapeutic window, the imatinib plasma quantification seems interesting to evaluate patient compliance to daily oral therapy, drug-drug interactions or pharmacokinetic/pharmacodynamic relationship. The aim of this study was to develop a simple and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the imatinib quantification, adapted to routine applications. After a liquid-liquid extraction, the imatinib and its deuterated internal standard were eluted on a XTerra® RP18 column with a gradient of acetonitrile-ammonium formiate buffer 4 mM pH 3.2. Imatinib was detected by electrospray ionisation mass spectrometry with multiple reaction monitoring mode. The calibration curves were linear over the range 10–5000 ng/ml. The limit of quantitation was set at 10 ng/ml. The bias was lower than 8 %. Intra-day and inter-day precisions were lower than 8 %. The extraction recovery was higher than 90 %.
The monitored population was defined as follows: patients treated for CML and receiving imatinib with one daily dose of 300, 400 or 600 mg. Blood samples were collected at steady state, 23 (±3) hours after drug administration, and were centrifuged at 4500 rpm for 5min. As shown on the figure 1, all patients treated with 600mg have a concentration more than 500 ng/ml which corresponds to the efficient concentration of imatinib according to the previously in vitro studies (i.e. the target plasma concentration required to induce the death of leukemic cells). Five patients - previously known as not having an efficient hematologic response or cytogenetic response showed an imatinib level lower than 500 ng/ml Two of these patients were not compliant and three patients were coadministered with enzymatic inducers: phenytoïn or phenobarbital or oxcarbazepine This method is simple, adapted to routine application and allows accurate therapeutic monitoring of imatinib. It can be used to evaluate patient adherence to daily oral therapy, drug-drug interactions or pharmacokinetic/pharmacodynamic relationship. In conclusion, regarding the definition imatinib resistance in CML, it seems necessary to take in account the value of the imatinib concentration. A study of correlation with the cytogenetic and molecular response is in progress.
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