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A Study on the Impact of Rabeprazole-induced Elevated Stomach pH on APO-Dabigatran Exposure in Healthy Volunteers

2019-11-14 17:39:49 | BioPortfolio

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.

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.

Study Design

Conditions

Atrial Fibrillation

Intervention

RABEprazole 20 Mg Oral Delayed Release Tablet, APO-Dabigatran 150mg

Status

Not yet recruiting

Source

Population Health Research Institute

Results (where available)

View Results

Links

Published on BioPortfolio: 2019-11-14T17:39:49-0500

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Medical and Biotech [MESH] Definitions

A THROMBIN inhibitor which acts by binding and blocking thrombogenic activity and the prevention of thrombus formation. It is used to reduce the risk of stroke and systemic EMBOLISM in patients with nonvalvular atrial fibrillation.

Impaired or delayed impulse conduction between the right and left HEART ATRIA. Advanced interatrial blocks are often associated with arrhythmias (e.g., ATRIAL FLUTTER; and ATRIAL FIBRILLATION), direct conduction block via the Bachmann's bundle and concomitant left atrial enlargement. Syndrome of advanced interatrial block associated with SUPRAVENTRICULAR TACHYCARDIA is referred to as Bayes syndrome.

Rapid, irregular atrial contractions caused by a block of electrical impulse conduction in the right atrium and a reentrant wave front traveling up the inter-atrial septum and down the right atrial free wall or vice versa. Unlike ATRIAL FIBRILLATION which is caused by abnormal impulse generation, typical atrial flutter is caused by abnormal impulse conduction. As in atrial fibrillation, patients with atrial flutter cannot effectively pump blood into the lower chambers of the heart (HEART VENTRICLES).

Long-term changes in the electrophysiological parameters and/or anatomical structures of the HEART ATRIA that result from prolonged changes in atrial rate, often associated with ATRIAL FIBRILLATION or long periods of intense EXERCISE.

Disturbance in the atrial activation that is caused by transient failure of impulse conduction from the SINOATRIAL NODE to the HEART ATRIA. It is characterized by a delayed in heartbeat and pauses between P waves in an ELECTROCARDIOGRAM.

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