Article: article from journal or magazin.
Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability
British Journal of Cancer
Imatinib has revolutionised the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST). Using a nonlinear mixed effects population model, individual estimates of pharmacokinetic parameters were derived and used to estimate imatinib exposure (area under the curve, AUC) in 58 patients. Plasma-free concentration was deduced from a model incorporating plasma levels of alpha(1)-acid glycoprotein. Associations between AUC (or clearance) and response or incidence of side effects were explored by logistic regression analysis. Influence of KIT genotype was also assessed in GIST patients. Both total (in GIST) and free drug exposure (in CML and GIST) correlated with the occurrence and number of side effects (e.g. odds ratio 2.7+/-0.6 for a two-fold free AUC increase in GIST; P<0.001). Higher free AUC also predicted a higher probability of therapeutic response in GIST (odds ratio 2.6+/-1.1; P=0.026) when taking into account tumour KIT genotype (strongest association in patients harbouring exon 9 mutation or wild-type KIT, known to decrease tumour sensitivity towards imatinib). In CML, no straightforward concentration-response relationships were obtained. Our findings represent additional arguments to further evaluate the usefulness of individualizing imatinib prescription based on a therapeutic drug monitoring programme, possibly associated with target genotype profiling of patients.
Adult, Aged, Antineoplastic Agents, Area Under Curve, Female, Gastrointestinal Stromal Tumors, Genotype, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Logistic Models, Male, Middle Aged, Multivariate Analysis, Odds Ratio, Piperazines, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Pyrimidines, Treatment Outcome
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