WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• 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• 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. AIMSImatinib 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 coadministered 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. METHODSTwelve 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. RESULTSPPI administration did not significantly affect the imatinib area under the plasma concentration vs time curve (AUC) (34.1 mg ml -1 h alone vs 33.1 mg ml -1 h with omeprazole, P = 0.64; 80% power), maximum plasma concentration (Cmax) (2.04 mg ml -1 alone vs 2.02 mg ml -1 with omeprazole, P = 0.97), or half-life (13.4 h alone vs 14.1 h with omeprazole, P = 0.13). CONCLUSIONSOur 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.

2503 Background: Imatinib mesylate, a potent inhibitor of Bcr-Abl and c-kit tyrosine kinases, is widely used to treat gastrointestinal stromal tumors and Philadelphia chromosome-positive leukemias. Imatinib often causes gastric upset and is therefore frequently administered with a proton pump inhibitor (PPI). Yet, the resulting elevated gastric pH, delayed gastric emptying, and inhibition of ABC transporters in the gut could change imatinib absorption, thereby affecting the therapeutic effectiveness of imatinib. To test this hypothesis, we sought to define the effect of PPI on the plasma pharmacokinetics of imatinib. Methods: 11 healthy subjects (6 M, 5 F; 21–56 years) were enrolled in a 2-period, open-label, randomized cross-over, fixed- sequence study. In one period, they received a single 400 mg dose of imatinib p.o., in the other, 40 mg omeprazol daily for five days followed by a single 400 mg dose of imatinib p.o.. The periods were separated by a wash-out period of ≥ 14 days. Plasma samples from 0–72 h after dosing were obtained. Plasma concentrations of imatinib and its active metabolite CGP74588 were determined with an LC-MS assay and data were analyzed non-compartmentally. The study was powered to detect a 30% difference in imatinib AUC with 80% power and a 5% type I error. Results: See Table . Conclusions: This study demonstrates that the use of PPI to treat imatinib-induced gastric upset does not significantly affect imatinib plasma AUC. Support: Novartis; NIH/NCRR/CTSA Grant UL1 RR024153 [Table: see text] [Table: see text]