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1.
Br J Clin Pharmacol ; 68(3): 370-4, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19740393

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 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.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Omeprazole/pharmacology , Piperazines/pharmacokinetics , Proton Pump Inhibitors/pharmacology , Pyrimidines/pharmacokinetics , Administration, Oral , Adult , Antineoplastic Agents/metabolism , Benzamides , Chromatography , Female , Humans , Imatinib Mesylate , Male , Mass Spectrometry , Piperazines/metabolism , Pyrimidines/metabolism
2.
Cancer Chemother Pharmacol ; 63(3): 525-8, 2009 Feb.
Article in English | MEDLINE | ID: mdl-18500518

ABSTRACT

PURPOSE: Imatinib often causes gastric upset resulting in frequent co-administration of an antacid. Elevated gastric pH, delayed gastric emptying, or introduction of Mg(2+)/Al(3+) could potentially change imatinib absorption, thereby affecting the therapeutic effectiveness of imatinib. Indeed, antacid co-administration with dasatinib does result in a twofold decrease in dasatinib absorption. We aimed to define the effect of antacid on the pharmacokinetics of imatinib. METHODS: Twelve healthy subjects were enrolled in a 2-period, open-label, randomized cross-over, fixed-sequence study. In one period, each subject received 400 mg imatinib p.o., and in the other, the same dose of imatinib preceded by 20 mL antacid, containing 1.6 g Al(OH)(3) + 1.6 g Mg(OH)(2), 15 min before imatinib. Plasma concentrations of imatinib and its active N-desmethyl metabolite CGP74588 were determined by LC-MS, and data were analyzed non-compartmentally. RESULTS: Antacid administration did not significantly affect the area under the plasma imatinib concentration versus time curve (AUC) [31.7 microg/(mL h) alone versus 32.6 microg/(mL h) with antacid, P = 0.37; 80% power]. CONCLUSIONS: Our results indicate that the use of Mg(2+)-Al(3+)-based antacid does not significantly affect imatinib absorption.


Subject(s)
Antacids/pharmacology , Antineoplastic Agents/pharmacokinetics , Piperazines/pharmacokinetics , Pyrimidines/pharmacokinetics , Adult , Antineoplastic Agents/blood , Area Under Curve , Benzamides , Cross-Over Studies , Drug Interactions , Female , Humans , Imatinib Mesylate , Male , Middle Aged , Piperazines/blood , Pyrimidines/blood
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