Pharmacokinetic-pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors.
OBJECTIVE
This study explored factors affecting the pharmacokinetic variability of imatinib and CGP 74588, and the pharmacokinetic-pharmacodynamic correlations in patients with advanced gastrointestinal stromal tumors.


METHODS
Thirty-five patients with advanced gastrointestinal stromal tumors received 400 mg of imatinib daily. Six blood samples were drawn: before intake, during 1- to 3- and 6- to 9-hour intervals after intake on day 1, and before intake on days 2, 30, and 60. Plasma imatinib and CGP 74588 concentrations were quantified by reverse-phase high-performance liquid chromatography coupled with tandem mass spectrometry, and analyzed by the population pharmacokinetic method (NONMEM program). The influence of 17 covariates on imatinib clearance (CL) and CGP 74588 clearance (CLM/fm) was studied. These covariates included clinical and biological variables and occasion (OCC = 0 for pharmacokinetic data corresponding to the first administration, or OCC = 1 for the day 30 or 60 administrations).


RESULTS
The best regression formulas were: CL (L/h) = 7.97 (AAG/1.15)(-0.52), and CLM/fm (L/h) = 58.6 (AAG/1.15)(-0.60) x 0.55(OCC), with the plasma alpha1-acid glycoprotein (AAG) levels indicating that both clearance values decreased at a higher AAG level. A significant time-dependent decrease in CLM/fm was evidenced with a mean (+SD) CGP 74588/imatinib area under the curve (AUC) ratio of 0.25 (+/-0.07) at steady state, compared with 0.14 (+/-0.03) on day 1. Hematologic toxicity was correlated with pharmacokinetic variables: the correlation observed with the estimated unbound imatinib AUC at steady-state (r = 0.56, P < 0.001) was larger than that of the total imatinib AUC (r = 0.32, NS).


CONCLUSIONS
The plasma AAG levels influenced imatinib pharmacokinetics. A protein-binding phenomenon needs to be considered when exploring the correlations between pharmacokinetics and pharmacodynamics.
Delbaldo
Catherine
C
Hospital Henri-Mondor, Créteil, France, EA3035, Institut Claudius-Regaud, Toulouse, France.
Chatelut
Etienne
E
Ré
Micheline
M
Deroussent
Alain
A
Séronie-Vivien
Sophie
S
Jambu
Aurore
A
Berthaud
Patrice
P
Le Cesne
Axel
A
Blay
Jean-Yves
JY
Vassal
Gilles
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D001549:Benzamides; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D018579:Patient Selection; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D015203:Reproducibility of Results
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate