LAUSR

Dabigatran is the first of four direct-acting oral anticoagulants approved to prevent stroke in adult patients with atrial fibrillation using a fixed 2-dose scheme compared to warfarin dosing adjusted to a prothrombin time range associated with optimal risk reduction in stroke and serious bleeding. The pivotal phase 3 trial found dabigatran, depending on dose, is superior to warfarin in stroke reduction and similar in bleeding risk while also showing dabigatran efficacy and safety correlate with steady-state plasma concentrations. Since the relationship between dabigatran dose and plasma concentration is highly variable, a previously developed population pharmacokinetic model of over 9,000 clinical trial patients was used as a basis for simulations comparing the performance of dosing via the drug label to other proposed doses and regimens. Assessment of dosing regimen performance was based on simulations of trough plasma levels within the therapeutic concentration range of 75-150 ng/mL over a renal function range of 15-250 mL/min creatinine clearance, representing extremes for real-world patients. An improved regimen that best achieves this therapeutic range was identified, requiring 5 different dosing schedules, corresponding to specified renal function ranges, compared to the 2 approved in the label. The discussion focuses on how this information could better inform patient outcomes and future dabigatran development.