Bioequivalence of a Newly Developed Dabigatran Etexilate Tablet Versus the Commercial Capsule and Impact of Rabeprazole-Induced Elevated Gastric pH on Exposure in Healthy Subjects

Abstract

Background and objective: Dabigatran etexilate (DE) is an anticoagulant with proven efficacy and tolerability for stroke prevention in patients with non-valvular atrial fibrillation. For the commercial capsule, a complex formulation is used to maintain the acidic microenvironment required for maximal absorption. Consequently, its efficacy and safety are similar with or without concomitant intake of proton-pump inhibitors (PPIs). A simplified DE tablet formulation was developed and tested in two studies. One investigated bioequivalence (BE) of the novel DE tablet versus the commercial DE capsule. The other investigated DE bioavailability (BA) under pretreatment with the PPI rabeprazole and assessed the effect of elevated pH on exposure to dabigatran.

Methods: BE of the novel DE tablet versus the DE capsule was assessed in a randomized two-treatment, four-period, two-sequence crossover study (NCT03070171). The effect of rabeprazole on the BA of the DE tablet was assessed in an open-label, single-arm study (NCT03143166). Both studies were conducted at sites in Japan. Participants were healthy male volunteers, aged ≥ 20-40 years. In the BE study, participants received the DE tablet or capsule (single oral dose, 110 mg); primary endpoints were area under the concentration-time curve from baseline to the last quantifiable data point (AUC0-tz) and maximum plasma concentration (Cmax) of unconjugated dabigatran. In the relative BA study, participants received the DE tablet (single oral dose, 110 mg) with or without rabeprazole pretreatment (once daily for 5 days, 20 mg); primary endpoints were AUC0-tz and Cmax of total dabigatran.

Results: In total, 160 participants were randomized in the BE study; 36 participants were enrolled in the BA study. The 90% confidence intervals of geometric mean (gMean) ratios for AUC0-tz (101.4-116.0%) and Cmax (101.8-116.6%) of unconjugated dabigatran were within pre-defined acceptance criteria for BE. In the relative BA study, the gMeans of AUC0-tz (667 to 192 ng h/mL) and Cmax (83.1 to 21.8 ng/mL) were decreased by approximately 70% when the tablet was administered under rabeprazole pretreatment. The reduction in BA was observed at a mean gastric pH of 5.3. Treatment was well tolerated; no deaths, serious adverse events (AEs) or significant AEs were reported in either study.

Conclusion: The DE tablet demonstrated BE to the capsule; however, at high gastric pH, BA of the tablet was reduced by approximately 70%, which may lead to reduced efficacy. Data indicate the importance of examining not only BE under standard conditions, but relative BA at elevated gastric pH. Such investigations may avoid the reduced BA at elevated pH that is quite common in the target population (the elderly and/or patients treated with gastric-acid modifying co-medications), and therefore reduce treatment failure with DE. Registration: ClinicalTrials.gov identifier numbers: NCT03070171, and NCT03143166.

Conflict of interest statement

Akiko Harada: employee of Nippon Boehringer Ingelheim Co., Ltd. Ippei Ikushima: no conflicts of interest to disclose. Miwa Haranaka: no conflicts of interest to disclose. Aki Yanagihara: employee of Nippon Boehringer Ingelheim Co., Ltd. Daisuke Nakayama: employee of Nippon Boehringer Ingelheim Co., Ltd.

Figures

Fig. 1

BE of the DE tablet versus capsule: randomization sequence and study design. There was a washout period of at least 4 days between treatment administrations. BE bioequivalence, DE dabigatran etexilate, R reference treatment: dabigatran etexilate commercial capsule formulation, T test treatment: dabigatran etexilate tablet formulation, N number of subjects

Fig. 2

BA of the DE tablet alone and under rabeprazole pretreatment: study design. BA bioavailability, DE dabigatran etexilate, EOT end of trial, N number of subjects. 1DE tablet was given 4 h after rabeprazole administration

Fig. 3

Mean (± SD) plasma concentration–time profiles of unconjugated dabigatran after a single 110-mg dose of DE tablet or capsule formulations. DE dabigatran etexilate, N number of subjects, SD standard deviation

Fig. 4

Mean (± SD) plasma concentration–time profiles of total dabigatran after a single 110-mg dose of DE alone or under 20-mg rabeprazole pretreatment. DE dabigatran etexilate, N number of subjects, SD standard deviation