Effect of antacid co-medication on imatinib disposition: A healthy volunteer study

Abstract

2547 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 an antacid (AA). Yet, the resulting elevated gastric pH, delayed gastric emptying, or introduction of Mg2+ and Al3+ could change imatinib absorption, thereby affecting the therapeutic effectiveness of imatinib. To test this hypothesis, we sought to define the effect of AA on the plasma pharmacokinetics of imatinib. Methods: 12 healthy subjects (6 M, 6 F; 20–51 years) were enrolled in a 2- period, open-label, randomized cross-over, fixed-sequence study. In one period, they received 400 mg imatinib p.o., in the other 20 mL Maximum Strength Maalox Max Antacid/Anti-gas (1.6 g Al(OH)3 + 1.6 g Mg(OH)2) 15 min prior to 400 mg 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 Mg2+-Al3+ based AA to treat imatinib-induced gastric upset does not significantly affect imatinib plasma AUC. The small difference in imatinib half-life, detected by an unplanned statistical test, should not affect the average steady-state concentration achieved after multiple doses, and therefore is not likely to be clinically significant. Support: Novartis; NIH/NCRR/CTSA Grant UL1 RR024153 Analyte Arm AUC0-inf Cmax tmax t1/2 V/F Cl/F (ug/mL*h) (ug/mL) (h) (h) (L) (L/h) Imatinib Alone 32.6 (8.0) 2.12 (0.43) 2.8 (0.9) 14.3 (1.5) 267 (75) 13.1 (3.7) Imatinib +AA 33.1 (6.0) 2.10 (0.45) 3.4 (0.7) 15.1 (1.8) 273 (72) 12.6 (3.1) p-value 0.73 0.85 0.08 0.03 0.68 0.40 CGP74588 Alone 6.04 (1.43) 0.27 (0.06) 2.5 (0.9) 30.5 (5.3) 3077 (945) 69.9 (17.1) CGP74588 +AA 6.45 (1.67) 0.26 (0.09) 3.1 (0.5) 33.3 (9.4) 3012 (1295) 61.2 (25.1) p-value 0.078 0.85 0.11 0.35 0.84 0.10 Mean (SD) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis