Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability.

@article{citeulike:2800269, 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 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 individualising imatinib prescription based on a therapeutic drug monitoring programme, possibly associated with target genotype profiling of patients.British Journal of Cancer (2008) 98, 1633-1640. doi:10.1038/sj.bjc.6604355 www.bjcancer.com Published online 6 May 2008.}, address = {1Division of Clinical Pharmacology, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.}, author = {Widmer, N. and Decosterd, L. A. and Leyvraz, S. and Duchosal, M. A. and Rosselet, A. and Debiec-Rychter, M. and Csajka, C. and Biollaz, J. and Buclin, T. }, citeulike-article-id = {2800269}, doi = {10.1038/sj.bjc.6604355}, issn = {0007-0920}, journal = {British journal of cancer}, keywords = {leukemia, treatment}, month = {May}, number = {10}, pages = {1633--1640}, posted-at = {2008-05-15 00:25:38}, priority = {5}, title = {Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability.}, url = {http://dx.doi.org/10.1038/sj.bjc.6604355}, volume = {98}, year = {2008} }

TY - JOUR ID - citeulike:2800269 L3 - citeulike-article-id:2800269 TI - Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability. JF - British journal of cancer VL - 98 IS - 10 SP - 1633 EP - 1640 AD - 1Division of Clinical Pharmacology, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. SN - 0007-0920 N2 - 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 individualising imatinib prescription based on a therapeutic drug monitoring programme, possibly associated with target genotype profiling of patients.British Journal of Cancer (2008) 98, 1633-1640. doi:10.1038/sj.bjc.6604355 www.bjcancer.com Published online 6 May 2008. KW - leukemia KW - treatment AU - Widmer, N AU - Decosterd, LA AU - Leyvraz, S AU - Duchosal, MA AU - Rosselet, A AU - Debiec-Rychter, M AU - Csajka, C AU - Biollaz, J AU - Buclin, T PY - 2008/05/20/ UR - http://dx.doi.org/10.1038/sj.bjc.6604355 ER -