Abstract
2526 Background: The aim of this study was to explore the impact of several demographic, biological and pharmacogenetic covariates on imatinib and its main metabolite (CGP74588) disposition. Methods: Thirty three children included in a phase 2 study and thirty four adults with gastrointestinal stromal tumor received 340 mg/m² and 400 mg imatinib, respectively. Plasma imatinib and CGP74588 concentrations observed on day 1 and at steady-state were analyzed by population pharmacokinetic method (NONMEM) to evaluate the impact of age, body weight (BW), age, sex, albuminemia (ALB), plasma alpha1-acid glycoprotein (AGP), and several polymorphisms corresponding to ABCB1, ABCG2, CYP3A4, CYP3A5, AGP (pharmacogenetic data available in 46/67 patients). Results: Analysis of the whole data set (67 patients) showed that apparent clearance (CL/F) of imatinib was positively correlated with BW and ALB, and negatively with AGP. By considering these three covariates, the inter-individual variability on CL/F decreased from 47...
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