A Study on the Impact of Rabeprazole-induced Elevated Stomach pH on APO-Dabigatran Exposure in Healthy Volunteers
Condition: Atrial Fibrillation; Venous Thromboembolism
MeSH terms: Atrial Fibrillation; Thromboembolism; Venous Thromboembolism
Study type: Interventional
Phase: Phase 4

Summary: 
      Open-label, crossover study recruiting 46 healthy male volunteers comparing the absorption of
      APO-dabigatran 150 mg per oral (PO) in the absence or presence of a proton pump inhibitor.
      Participants will serve as their own control when comparing dabigatran exposure in the
      absence or presence of the proton pump inhibitor, Rabeprazole 20 mg.
    

Detailed description: 
      Non-valvular atrial fibrillation (AF) and venous thromboembolism (VTE) affect hundreds of
      thousands of Canadians and many millions worldwide. Affected patients are routinely treated
      with oral anticoagulants. Vitamin K antagonists (VKAs) were the only orally available
      anticoagulants for more than 60 years. Over the past decade, Direct Acting Oral
      Anticoagulants (DOACs) have increasingly replaced VKAs for treatment of patients with AF or
      VTE because of similar or superior efficacy and safety, and greater convenience. One of these
      new agents, dabigatran etexilate, has now come off patent in Canada, and at least one generic
      made by Apotex has been approved by Health Canada.

      Prior to their introduction into clinical use, the development of an orally active direct
      thrombin inhibitors (DTIs) proved technically difficult because it required the conversion of
      a small, water soluble, poorly absorbable, active site-directed molecule into a fat-soluble
      prodrug that is transformed back to the active drug after intestinal absorption. In the case
      of dabigatran, this was achieved by administering it as an oral prodrug, dabigatran
      etexilate. When administered as the pro-drug, the bioavailability of dabigatran is
      pH-dependent and is optimal at low pH. To overcome the issue with pH-dependency of drug
      absorption, dabigatran capsules contain drug pellets, which are made up of a tartaric acid
      core coated with dabigatran etexilate, thereby maintaining an acid micro-environment (1, 2).
      After absorption the prodrug is metabolized to the active form dabigatran through esterases
      that are ubiquitous in the body.

      Many patients taking oral anticoagulants are elderly and have an increased gastric pH (3),
      often as a result of commonly prescribed co-medications such as proton pump inhibitors
      (PPIs). Optimization of the formulation of originator Pradaxa® (dabigatran etexilate)
      provides consistent absorption in elderly patients, independent of gastric pH (1, 4), as was
      demonstrated in phase III trials where consistent outcomes were achieved in the young and
      elderly, and in the presence and absence of PPI therapy(5).

      Generic formulations of dabigatran etexilate are required to demonstrate bioequivalence to
      the originator in healthy volunteers in order to receive regulatory approval in Canada.
      According to Canadian regulations and Health Canada, bioequivalence trials do not usually
      require testing in older patients with an altered gastric pH or in patients taking a PPI (6).
      The sophisticated pharmaceutical formulation of Pradaxa® ensures stable and reliable
      absorption despite its low solubility under elevated pH. Pradaxa® has a bioavailability of
      6.5% (4, 7) and even any seemingly small alteration in absorption resulting from a change in
      formulation may significantly affect drug levels. Lower drug levels could lead to an increase
      in thrombotic events, and higher drug levels could increase bleeding. The European Union (EU)
      product specific guideline for dabigatran etexilate, however, does require additional
      bioequivalence studies with elevated gastric pH by means of PPI pre-treatment(8).

      APO-Dabigatran is one of the first generic formulations of dabigatran etexilate to be
      introduced into the Canadian market. APO-Dabigatran compared with Pradaxa® demonstrated
      similar bioavailability in healthy volunteers, fulfilling the requirements as a generic
      alternative to the original compound. Unlike Pradaxa®, APO-Dabigatran is formulated using
      fumaric acid and it is unclear whether this produces a similar pharmacokinetic profile to
      that of Pradaxa in patients with altered gastric pH, for example in the elderly or those
      taking a PPI.

      This study objective is to determine in healthy volunteers whether concomitant PPI therapy
      impairs absorption of APO-dabigatran 150 mg and thereby reduces drug blood levels.
    

Intervention name(s): RABEprazole 20 Mg Oral Delayed Release Tablet; APO-Dabigatran 150mg
Intervention type(s): Drug; Drug
Intervention description(s): Absorption of APO-Dabigatran measured with and without influence of rabeprazole; Absorption of APO-Dabigatran post single dose
Intervention MeSH terms: Rabeprazole; Dabigatran
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Prevention