Effect of a proton pump inhibitor on the pharmacokinetics of imatinib

center dot Gastric upset is a side-effect of imatinib therapy and the concomitant use of proton pump inhibitors is common. With the increase in oral chemotherapy in cancer treatment, oral drug-drug interactions are becoming more relevant, as is exemplified by dasatinib which has already been shown to be absorbed to a much lesser extent when co-administered with antacids or proton-pump inhibitors. Because exposure to subtherapeutic concentrations of anticancer drugs such as imatinib and dasatinib may result in selection of resistant clones, and ultimately relapse, we studied the effect of the proton pump inhibitor omeprazole on the pharmacokinetics of imatinib. WHAT THIS STUDY ADDS center dot Omeprazole may be co-administered with imatinib to treat the gastric side-effects of the latter without affecting the pharmacokinetics of imatinib and risking tumour relapse. AIMS Imatinib mesylate (Gleevec (R)/Glivec (R)), 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 (R)) 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 mu g ml(-1) h alone vs 33.1 mu g ml(-1) h with omeprazole, P = 0.64; 80% power), maximum plasma concentration (C-max) (2.04 mu g ml(-1) alone vs 2.02 mu g 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.