Clinical consequences of imatinib plasma concentrations variability in hemato-oncologic patients

Details

Serval ID
serval:BIB_B0F78B154ADC
Type
Inproceedings: an article in a conference proceedings.
Publication sub-type
Abstract (Abstract): shot summary in a article that contain essentials elements presented during a scientific conference, lecture or from a poster.
Collection
Publications
Institution
Title
Clinical consequences of imatinib plasma concentrations variability in hemato-oncologic patients
Author(s)
Widemer Nicolas, Leyvraz Serge, Duchosal Michel A., Rosselet Anne, Csajka Chantal, Henry Hugues, Debiec-Rychter Maria, Eap Chin-Bin, Biollaz Jérôme, Buclin Thierry, Décosterd Laurent A.
ISBN
0163-4356
Publication state
Published
Issued date
2007
Peer-reviewed
Oui
Volume
29
Series
Therapeutic Drug Monitoring
Pages
481
Language
english
Notes
SAPHIRID:64697
Abstract
Background: Imatinib has revolutionized the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). Considering the large inter-individual differences in the function of the systems involved in its disposition, exposure to imatinib can be expected to vary widely among patients. This observational study aimed at describing imatinib pharmacokinetic variability and its relationship with various biological covariates, especially plasma alpha1-acid glycoprotein (AGP), and at exploring the concentration-response relationship in patients.
Methods: A population pharmacokinetic model (NONMEM) including 321 plasma samples from 59 patients was built up and used to derive individual post-hoc Bayesian estimates of drug exposure (AUC; area under curve). Associations between AUC and therapeutic response or tolerability were explored by ordered logistic regression. Influence of the target genotype (i.e. KIT mutation profile) on response was also assessed in GIST patients.
Results: A one-compartment model with first-order absorption appropriately described the data, with an average oral clearance of 14.3 L/h (CL) and volume of distribution of 347 L (Vd). A large inter-individual variability remained unexplained, both on CL (36%) and Vd (63%), but AGP levels proved to have a marked impact on total imatinib disposition. Moreover, both total and free AUC correlated with the occurrence and number of side effects (e.g. OR 2.960.6 for a 2-fold free AUC increase; p,0.001). Furthermore, in GIST patients, higher free AUC predicted a higher probability of therapeutic response (OR 1.960.5; p,0.05), notably in patients with tumor harboring an exon 9 mutation or wild-type KIT, known to decrease tumor sensitivity towards imatinib.
Conclusion: The large pharmacokinetic variability, associated to the pharmacokinetic-pharmacodynamic relationship uncovered are arguments to further investigate the usefulness of individualizing imatinib prescription based on TDM. For this type of drug, it should ideally take into consideration either circulating AGP concentrations or free drug levels, as well as KIT genotype for GIST.
Create date
10/03/2008 10:54
Last modification date
20/08/2019 15:19
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