Influence of H2-receptor antagonists and proton pump inhibitors on dasatinib pharmacokinetics in Japanese leukemia patients

Abstract

The objective of this study was to investigate the drug interaction between dasatinib and the gastric acid suppressants (H2-receptor antagonists (H2RA) famotidine and nizatidine and the proton pump inhibitor (PPI) lansoprazole in leukemia Japanese patients. Eighteen patients treated with dasatinib and H2RA, PPI or no acid suppressant from whom were obtained a total of 34 pharmacokinetic profiles were enrolled in the study. Dasatinib plasma concentrations from samples obtained just prior to and 1, 2, and 4 h after oral dasatinib administration were analyzed by high-performance liquid chromatography. There were no significant correlations between the dose-adjusted total area under the observed plasma concentration-time curve (AUC(0-4)) of dasatinib and gender, age, weight, or body surface area. The only variable factor, the dasatinib dose-adjusted AUC(0-4) for patients administered an H2RA or PPI, was significantly lower than for patients not administered an acid suppressant (median (quartile 1-quartile 3) values: 1.47 (0.79-2.29) versus 3.51 (2.50-5.45) ng h/mL/mg, respectively, P = 0.0008). Moreover, the plasma concentration 2 h (C(2h)) after dasatinib administration gave a high correlation with the AUC(0-4) of dasatinib (r = 0.9419, P < 0.0001). Clinicians should be aware that administration of an acid suppressant such as famotidine, nizatidine, and lansoprazole can decrease the absorption of dasatinib from the gastrointestinal tract, thereby resulting in a significant decrease in the plasma concentration of dasatinib. The combination of dasatinib and an acid suppressant requires careful therapeutic drug monitoring of the dasatinib plasma concentration to ensure effective patient exposure to the drug.