Exposure- response for biomarkers of anticoagulant effects by the oral direct thrombin inhibitor AZD0837 in patients with atrial fibrillation (original) (raw)

AZD0837 is a novel oral anticoagulant investigated in clinical studies for stroke prevention in patients with atrial fibrillation (AF). It is bioconverted to its active form, AR-H067637, a potent, specific and reversible thrombin inhibitor. A population pharmacokinetic (PK) analysis was performed and the effect of AZD0837 therapy on fibrin D-dimer levels was correlated to the PK exposure of AR-H067637, as well as the effect on thrombin generation measured ex vivo, to guide selection of the effective dose regimen for a confirmatory efficacy study in AF patients. Blood samples were obtained from 601 AF patients randomized to receive 1 of 4 doses of AZD0837 (blinded treatment) or dose-adjusted vitamin K antagonists (VKA, open treatment) for 3-9 months. A pharmacodynamic model was developed to describe time course of the AR-H067637 exposure dependent effects and the effect of VKA on fibrin D-dimer. The concentration-effect relationship for thrombin generation measured ex vivo in venous ...