Interventional - Drug
Background: Optimization of the formulation of Pradaxa® (Dabigatran etexilate) provides consistent absorption in patients, independent of gastric pH. This has been demonstrated in clinical trials, where clinical outcomes with and without proton pump inhibitors (PPIs) were evaluated and shown to be equivalent. Many patients taking oral anticoagulants are elderly and have an increased gastric pH, often through commonly prescribed comedications such as PPIs. Generic formulations of dabigatran etexilate are required to demonstrate bioequivalence (BE) to the originator in young healthy volunteers to receive regulatory approval in Canada. One generic currently on the market in Canada is produced by Apotex Inc. (APO-Dabigatran). Apotex Inc. have changed the acid in the tablet from tartaric to fumaric. They were, however, not required to demonstrate the same BE in those with an altered gastric pH such as older patients or on comedications (e.g. PPIs).
Objective: To determine any influence of PPIs on absorption of generic dabigatran available in Canada.
Methodology: Healthy male volunteers will participate in the study. All procedures performed will be done in accordance with the ethical standards of the institutional research committee and according to the declaration of Helsinki. All participants will provide written informed consent.
APO-dabigatran will be used for an open, cross-over design in up to 50 volunteers who will receive a single dose of 150 mg. Blood samples will be taken at defined time points: 0/trough, 30, 60, and 90 min and 2, 3, 4, 6, 8, and 24 h after administration. Volunteers will then undergo a wash-out period (4 days) while taking a PPI once daily (rabeprazole). On day 5, a repeat single APO-dabigatran 150 mg tablet will be administered in addition to the PPI. Blood sampling will occur as performed previously.
Assessment and Endpoints: Dabigatran levels for APO-dabigatran (total and active metabolite) will be the assessment for the area under the concentration–time curve from baseline to the last quantifiable data point (AUC0–tz), and the maximum plasma concentration (Cmax) of total, with or without PPI. Secondary outcomes include dabigatran-specific assays such as diluted thrombin time (dTT) and aPTT. Safety will be assessed throughout the study by: frequency of AEs and vital signs (blood pressure, pulse rate).
Interventional - Drug
Open-label crossover study
John Eikelboom is Associate Professor in the Department of Medicine, McMaster University, and a haematologist in the Thrombosis Service, Hamilton General Hospital. He originally trained in Internal Medicine and Haematology in Perth, Australia and subsequently moved to Hamilton to take up a Tier II Canada Research Chair in Cardiovascular Medicine.
He has co-authored more than 350 articles in peer-reviewed journals. His current research, supported by the Canadian Institutes for Health Research, the Heart and Stroke Foundation and the National Health and Medical Research Council of Australia, focuses on the efficacy and safety of antithrombotic therapies, outcomes after blood transfusion and bleeding, and the mechanisms of variable response to antiplatelet drugs.
Sumathy Rangarajan has been Program Director, Global Health, since 2016, preceded by many years’ service at PHRI in other roles. She oversees the PURE study team, as well as the INVICTUS rheumatic AF treatment trial, the CANPWR pediatric weight management registry, and others.
She holds both a Bachelor of Science Degree and a Master of Science degree from Pune University in India.
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