Impact of Rabeprazole on APO-Dabigatran Exposure in Healthy Volunteers

BACKGROUND: Dabigatran is effective and safe for stroke prevention in patients with atrial fibrillation and for venous thromboembolism prevention and treatment. In Canada, APO-dabigatran, a generic formulation, has been approved based on a bioequivalence study, but its bioavailability in settings of reduced gastric acidity has not been examined. METHODS: Treatment With APO-Dabigatran Absorption (TADA) was an open-label crossover study in 46 healthy male volunteers, comparing the absorption of APO-dabigatran (150 mg) with vs without rabeprazole. The primary outcome was the 24-hour total dabigatran exposure as measured by area under the curve (AUC) and peak concentration (C(max)). RESULTS: Compared with no rabeprazole pretreatment, the total dabigatran AUC (geometric mean [gmean] AUC(0-tz): 567.2 vs 804 ngh/mL, and gmean AUC(0-∞): 609.7 vs 804) and C(max) (gmean: 64.1 vs 104.4 ng/mL) were significantly reduced with rabeprazole. The percent gmean ratios for AUC(0-tz), AUC(0-∞), and C(max) (with rabeprazole vs without) were 70.5% (95% confidence interval [CI]: 51.9% to 95.7%), 71.8% (95% CI: 53.1% to 96.9%), and 61.4% (95% CI: 44.1% to 85.5%), respectively. With rabeprazole, the proportions of participants with > 50% reduction in AUC(0-tz,) AUC(0-∞,) and C(max) were 32.6%, 30.4%, and 39.1%, respectively CONCLUSIONS: When APO-dabigatran is administered with rabeprazole, the exposure to dabigatran is reduced by about 30%, which is similar to the level observed with Pradaxa when it was co-administered with a proton pump inhibitor. However, the finding that one-third of participants had a > 50% reduction in exposure is concerning, and it highlights the need for caution in patients who have, or are at risk of, reduced gastric acidity.