Exposure–response for biomarkers of anticoagulant effects by the oral direct thrombin inhibitor AZD0837 in patients with atrial fibrillation

Abstract

AIMSAZD0837 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. The effects on coagulation biomarkers were correlated with the pharmacokinetic (PK) exposure of AR-H067637 to guide selection of the effective dose regimen for a confirmatory efficacy study in AF patients. METHODSBlood samples were obtained from 601 AF patients randomized to one of four 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 the time course of the AR-H067637 exposure dependent effects and the effect of VKA on fibrin D-dimer. The thrombin generation measured ex vivo in venous plasma was also investigated. RESULTSThe PK exposure of AR-H067637 was stable with an interindividual variability of 33% and no or minor influence of patient demographics or comedications. For AZD0837, D-dimer levels decreased with more rapid onset than for VKA. The decrease in D-dimer levels correlated with steady-state plasma concentrations (C ss ) of AR-H067637, with a maximum decrease of baseline D-dimer levels estimated to approximately 60% for both AZD0837 and VKA therapy. The effect on thrombin generation correlated closely with the plasma concentration of AR-H067637. CONCLUSIONSThe effects on thrombin generation and fibrin D-dimer levels correlated with the plasma concentration of its active form and provided comparable effects to well-controlled VKA therapy at an exposure at least corresponding to the 300 mg once daily dose of AZD0837. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• AZD0837 is a novel oral anticoagulant that after bioconversion to its active form is a potent and reversible thrombin inhibitor.• Effects of AZD0837 treatment on thrombin generation and fibrin D-dimer levels were investigated and compared with the effect of vitamin K antagonist (VKA) therapy (INR 2.0-3.0, in a phase II dose-guiding study.• Thrombin generation and fibrin D-dimer are biomarkers of target activation and thrombogenicity, respectively WHAT THIS STUDY ADDS• The PK of the active form of AZD0837 was stable with no or minor influence of patient demographic factors and comedications.• Following oral therapy with AZD0837, inhibitory effects on thrombin generation and fibrin D-dimer levels were correlated with the plasma concentration of its active form.• At an exposure at least corresponding to the 300 mg once daily dose, AZD0837 provided comparable effects to wellcontrolled VKA therapy.