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


CONCLUSIONS
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.
Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
Amina
A
Haouala
Nicolas
N
Widmer
Monia
M
Guidi
Michael
M
Montemurro
Serge
S
Leyvraz
Thierry
T
Buclin
Chin B
CB
Eap
Laurent A
LA
Decosterd
Chantal
C
Csajka
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000097:blood* / Q000493:pharmacokinetics*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000097:blood*; D046152:Gastrointestinal Stromal Tumors / Q000097:blood*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009961:Orosomucoid / Q000378:metabolism; D010879:Piperazines / Q000097:blood* / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000097:blood* / Q000493:pharmacokinetics*; D012709:Serum Albumin / Q000378:metabolism
D001549:Benzamides; D009961:Orosomucoid; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012709:Serum Albumin; D000068877:Imatinib Mesylate