Twice daily dosing of dabigatran for stroke prevention in atrial fibrillation: a pharmacokinetic justification

Abstract

Background and objective:Dabigatran is a new oral anticoagulant recently approved for the prevention of stroke or systemic embolism in patients with atrial fibrillation (AF). Based on its pharmacokinetic profile, dabigatran is dosed twice daily. This analysis provides a quantitative rationale for the selection of the dose regimen in this population.Methods:The pharmacokinetic profile of dabigatran was simulated for AF patients given a total daily dose of 300 mg, either once or twice daily. Simulations were based on a population pharmacokinetic model supplemented with data collected from 9522 patients enrolled in a pivotal phase III study (RE-LY).Results:The typical RE-LY patient (male, 72 years old, Caucasian, weight 80 kg, creatinine clearance 68.64 mL/min) treated with dabigatran 150 mg twice daily showed less than two-fold difference between peak–trough plasma levels compared with a five-fold difference when the same total dose (300 mg) was administered once daily. For patients who miss or delay taking one scheduled dabigatran dose, twice daily dosing maintained adequate minimum trough concentrations better than once daily dosing. Pharmacokinetic data collected from a phase II study and RE-LY were consistent with the simulation results. The study did not access comparative efficacy and bleeding data for once versus twice daily dosing.Conclusion:Pharmacokinetic simulations show that a twice daily regimen in patients with AF minimizes daily fluctuations in plasma concentrations of dabigatran and can maintain trough concentrations sufficient to prevent the development of thrombi while at the same time minimizing the risk of bleeding due to supratherapeutic peak plasma concentrations. The efficacy and safety of this dosing regimen is supported by clinical data from the RE-LY trial.