Effect of a proton pump inhibitor on the pharmacokinetics of imatinib

Merrill J Egorin,1,2,3 Dhvani D Shah,1 Susan M Christner,1 Mara A Yerk,4 Kristin A Komazec,4 Leonard R Appleman,2 Robert L Redner,2 Brian M Miller,5 and Jan H Beumer1,6

Abstract
AIMS

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 µg ml−1 h alone vs 33.1 µg ml−1 h with omeprazole, P= 0.64; 80% power), maximum plasma concentration (Cmax) (2.04 µg ml−1 alone vs 2.02 µg 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 Cmax two-fold

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766475/