Dataset Information

Impact of Rabeprazole on APO-Dabigatran Exposure in Healthy Volunteers.

ABSTRACT:

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.

SUBMITTER: Chan N

PROVIDER: S-EPMC9869351 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Impact of Rabeprazole on APO-Dabigatran Exposure in Healthy Volunteers.

Chan Noel N Wheeler Matt M Bhagirath Vinai V Bosch Jacqueline J Heinrich-Nols Jutta J Sloane Debbie D van Ryn Joanne J Jefferies Linda L Wilkinson Jacqueline J Yi Qilong Q Eikelboom John J

CJC open 20221012 1

<h4>Background</h4>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.<h4>Methods</h4>Treatment With <b>A</b>PO-<b>D</b>abigatran <b>A</b>bsorption (TADA) was an open-label crossover study in 46 healthy male voluntee ...[more]

PMID: 36700178

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Project description:Background and objectiveDabigatran 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.MethodsBE 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.ResultsIn 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.ConclusionThe 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.

Project description:BackgroundDabigatran etexilate is a pro-drug of the oral reversible direct thrombin inhibitor dabigatran that interacts with the active site in the catalytic domain of the thrombin molecule.ObjectiveTo assess the electrophysiological effects of therapeutic and supratherapeutic doses of dabigatran etexilate in healthy subjects, a thorough QT study was performed.MethodsIn this single-centre, blinded, placebo- and active-controlled, four-period, crossover study, 40 healthy Caucasian subjects (20 women and 20 men) received single oral doses of dabigatran etexilate (150 mg and 600 mg), moxifloxacin 400 mg (positive control) or placebo, in a randomized order. Electrocardiogram (ECG) profiles were recorded at baseline and during the randomized study treatment in each period. The individually heart-rate-corrected QT interval (QTcI) was the primary parameter. The primary endpoint was the mean of these QTcI values obtained at 1.5, 2 and 3 h following study drug administration minus the mean of the time-matched QTcI values obtained at baseline day -1. The hypothesis tested was that the difference between each of the two doses of dabigatran etexilate (150 mg and 600 mg) and placebo, for the mean time-matched change from baseline (CfB) of QTcI between 1.5 and 3 h (the primary endpoint), was greater than or equal to 10 ms. Secondary endpoints were the time-matched CfB of QTcI between 0.5 and 24 h post-dose.ResultsAll subjects completed the study without premature discontinuation and all treatments were well tolerated. Following dabigatran etexilate administration, the mean values of the placebo-adjusted time-matched CfB of QTcI between 1.5 and 3 h post-dose were close to 0; the upper bound of the two-sided 90 % confidence interval (CI) was 1.4 ms for dabigatran etexilate 150 mg and 1.3 ms for dabigatran etexilate 600 mg. The placebo-adjusted time-matched CfB of QTcI remained close to 0 at all time points, and all 90 % CIs were between -5 ms and 5 ms, well below the pre-defined non-inferiority margin of 10 ms.ConclusionThis thorough QT study demonstrated that therapeutic and fourfold supratherapeutic doses of dabigatran etexilate do not prolong QT intervals.

Dataset Information

Impact of Rabeprazole on APO-Dabigatran Exposure in Healthy Volunteers.

Background

Methods

Results

Conclusions

Publications

Impact of Rabeprazole on APO-Dabigatran Exposure in Healthy Volunteers.

Similar Datasets

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