serval:BIB_5285F3FECE13
Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability
10.1038/sj.bjc.6604355
000255897800007
18475296
Widmer
N.
author
Decosterd
L. A.
author
Leyvraz
S.
author
Duchosal
M. A.
author
Rosselet
A.
author
Debiec-Rychter
M.
author
Csajka
C.
author
Biollaz
J.
author
Buclin
T.
author
article
2008
British Journal of Cancer
1532-1827
journal
98
10
1633-1640
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
eng
60_published
true
peer-reviewed
University of Lausanne
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