1. ¹Division of Clinical Pharmacology, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
2. ²Multidisciplinary Oncology Centre, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
3. ³Service of Haematology, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
4. ⁴Department of Human Genetics, University of Leuven and University Hospital Gasthuisberg, Leuven, Belgium

Correspondence: Dr N Widmer, Division of Clinical Pharmacology and Toxicology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Hôpital Beaumont 06.605, Lausanne CH-1011, Switzerland. E-mail: Nicolas.Widmer@chuv.ch

Revised 13 March 2008; Accepted 20 March 2008; Published online 6 May 2008.

Abstract

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 alpha₁-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 2.70.6 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 2.61.1; 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 individualising imatinib prescription based on a therapeutic drug monitoring programme, possibly associated with target genotype profiling of patients.