Pharmacokinetic Investigation of Imatinib Using Accelerator Mass Spectrometry in Patients with Chronic Myeloid Leukemia

Abstract

Purpose:To investigate the potential use of accelerator mass spectrometry (AMS) in the study of the clinical pharmacology of imatinib. Experimental Design: Six patients who were receiving imatinib (400 mg/d) as part of their ongoing treatment for chronic myeloid leukemia (CML) received a dose containing a trace quantity (13.6 kBq) of 14 C-imatinib. Blood samples were collected from patients before and at various times up to 72 h after administration of the test dose and were processed to provide samples of plasma and peripheral blood lymphocytes (PBL). Samples were analyzed by AMS, with chromatographic separation of parent compound from metabolites. In addition, plasma samples were analyzed by liquid chromatography/mass spectrometry (LCMS). Results: Analysis of the AMS data indicated that imatinib was rapidly absorbed and could be detected in plasma up to 72 h after administration. Imatinib was also detectable in PBL at 24 h after administration of the 14 C-labeled dose. Comparison of plasma concentrations determined by AMS with those derived by LCMS analysis gave similar average estimates of area under plasma concentration time curve (26 F 3 versus 27 F 11 Ag/mLÁh), but with some variation within each individual. Conclusions: Using this technique, data were obtained in a small number of patients on the pharmacokinetics of a single dose of imatinib in the context of chronic dosing, which could shed light on possible pharmacologic causes of resistance to imatinib in CML.

Imatinib and Norimatinib Plasma Levels Analyses of Chronic Myeloid Leukemia Patients

“…Mathematical average of imatinib transformation percentage to norimatinib was 22.16%, which aggress with the interval reported in previous studies. 5,6,10 Some patients revealed either high or low results. Differences in plasma drug and active primary metabolite levels showed a possible variability of the pharmacokinetic properties of imatinib from one patient to the other.…”

“…Nevetheless, norimatinib transformation was 12.20%, within the expected range. 5,6,10 He was on concomitant losartan treatment at the date of sample collection. Losartan is expected to increase exposure to imatinib.…”

“…Therefore, the analysis was performed in accordance with the 10-30% interval discussed in various studies. 5,6,10 Statistical analysis resulted in a mean age of 46.975±13.150 and 4.292±3.156 years of mean period of treatment. Mean plasma imatinib and norimatinib levels were 4.038±1.290 ppm and 1.150±0.733 ppm, respectively.…”

“…Young patients and elderly patients in the same group revealed 27.54% and 19.02% percentage transformation of imatinib to norimatinib, which falls within the range of results obtained in previous studies. 5,6,10 In our study, 5 years of treatment period was considered as a threshold in comparing short and long period results. Imatinib treatment period was not found to be statistically significant in relation to the imatinib and norimatinib levels.…”

“…[1][2][3] Imatinib is a targeted, potent and competitive TKI; it is designed to selectively interfere with key signal transduction pathways. [4][5][6] It performs its therapeutic activity on CML by competitive inhibition at the ATP-binding site. 4,7,8 This way, tyrosine kinase phosphorylation of proteins acting in Bcr-Abl signal transduction is inhibited.…”