Prediction of free imatinib concentrations based on total plasma concentrations in patients with gastrointestinal stromal tumours.

Details

Ressource 1Request a copy Sous embargo indéterminé.
State: Public
Version: author
Serval ID
serval:BIB_CF51D91AAB14
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Prediction of free imatinib concentrations based on total plasma concentrations in patients with gastrointestinal stromal tumours.
Journal
British Journal of Clinical Pharmacology
Author(s)
Haouala A., Widmer N., Guidi M., Montemurro M., Leyvraz S., Buclin T., Eap C.B., Decosterd L.A., Csajka C.
ISSN
1365-2125 (Electronic)
ISSN-L
0306-5251
Publication state
Published
Issued date
2013
Peer-reviewed
Oui
Volume
75
Number
4
Pages
1007-1018
Language
english
Notes
Publication types: Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
Abstract
AIM: Total imatinib concentrations are currently measured for the therapeutic drug monitoring of imatinib, whereas only free drug equilibrates with cells for pharmacological action. Due to technical and cost limitations, routine measurement of free concentrations is generally not performed. In this study, free and total imatinib concentrations were measured to establish a model allowing the confident prediction of imatinib free concentrations based on total concentrations and plasma proteins measurements.
METHODS: One hundred and fifty total and free plasma concentrations of imatinib were measured in 49 patients with gastrointestinal stromal tumours. A population pharmacokinetic model was built up to characterize mean total and free concentrations with inter-patient and intrapatient variability, while taking into account α1 -acid glycoprotein (AGP) and human serum albumin (HSA) concentrations, in addition to other demographic and environmental covariates.
RESULTS: A one compartment model with first order absorption was used to characterize total and free imatinib concentrations. Only AGP influenced imatinib total clearance. Imatinib free concentrations were best predicted using a non-linear binding model to AGP, with a dissociation constant Kd of 319 ng ml(-1) , assuming a 1:1 molar binding ratio. The addition of HSA in the equation did not improve the prediction of imatinib unbound concentrations.
CONCLUSION: Although free concentration monitoring is probably more appropriate than total concentrations, it requires an additional ultrafiltration step and sensitive analytical technology, not always available in clinical laboratories. The model proposed might represent a convenient approach to estimate imatinib free concentrations. However, therapeutic ranges for free imatinib concentrations remain to be established before it enters into routine practice.
Keywords
Adult, Aged, Aged, 80 and over, Benzamides/blood, Benzamides/pharmacokinetics, Female, Gastrointestinal Neoplasms/blood, Gastrointestinal Stromal Tumors/blood, Humans, Male, Middle Aged, Models, Biological, Orosomucoid/metabolism, Piperazines/blood, Piperazines/pharmacokinetics, Protein Kinase Inhibitors/blood, Protein Kinase Inhibitors/pharmacokinetics, Pyrimidines/blood, Pyrimidines/pharmacokinetics, Serum Albumin/metabolism
Pubmed
Web of science
Create date
28/08/2012 13:45
Last modification date
20/08/2019 16:49
Usage data