Effect of a proton pump inhibitor on the pharmacokinetics of imatinib.
OBJECTIVE
Imatinib mesylate (Gleevec/Glivec), which has revolutionized the treatment of chronic myeloid leukemias (CML) and gastrointestinal stromal tumours (GIST), has been reported to cause gastric upset. Consequently, proton pump inhibitors (PPI) are frequently co-administered with imatinib. Because PPI can elevate gastric pH and delay gastric emptying or antagonize ATP-binding-cassette transporters, they could influence imatinib absorption and pharmacokinetics. We aimed to evaluate whether use of omeprazole has a significant effect on imatinib pharmacokinetics.


METHODS
Twelve healthy subjects were enrolled in a two-period, open-label, single-institution, randomized cross-over, fixed-schedule study. In one period, each subject received 400 mg imatinib orally. In the other period, 40 mg omeprazole (Prilosec) was administered orally for 5 days, and on day 5 it was administered 15 min before 400 mg imatinib. Plasma concentrations of imatinib and its active N-desmethyl metabolite CGP74588 were assayed by LC-MS, and data were analyzed non-compartmentally.


RESULTS
PPI administration did not significantly affect the imatinib area under the plasma concentration vs time curve (AUC) (34.1 microg ml(-1) h alone vs 33.1 microg ml(-1) h with omeprazole, P= 0.64; 80% power), maximum plasma concentration (C(max)) (2.04 microg ml(-1) alone vs 2.02 microg ml(-1) with omeprazole, P= 0.97), or half-life (13.4 h alone vs 14.1 h with omeprazole, P= 0.13).


CONCLUSIONS
Our results indicate that the use of omeprazole does not significantly affect the pharmacokinetics of imatinib, as opposed to, for example, dasatinib where PPI decreased AUC and C(max) two-fold.
Egorin
Merrill J
MJ
Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213-1863, USA.
Shah
Dhvani D
DD
Christner
Susan M
SM
Yerk
Mara A
MA
Komazec
Kristin A
KA
Appleman
Leonard R
LR
Redner
Robert L
RL
Miller
Brian M
BM
Beumer
Jan H
JH
D000284:Administration, Oral; D000328:Adult; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001549:Benzamides; D002845:Chromatography; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D013058:Mass Spectrometry; D009853:Omeprazole / Q000494:pharmacology*; D010879:Piperazines / Q000378:metabolism / Q000493:pharmacokinetics*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000378:metabolism / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D054328:Proton Pump Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D009853:Omeprazole