title: Exposure-response for biomarkers of anticoagulant effects by the oral direct thrombin inhibitor AZD0837 in patients with atrial fibrillation.
abstract: OBJECTIVE
  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. 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.
  
  
  METHODS
  Blood 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom.|Thrombosis Research Centre, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
authors.forename: Gregory Y H
authors.initials: GY
authors.lastname: Lip
authors.affiliation: Thrombosis Research Centre, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
authors.forename: Lars H
authors.initials: LH
authors.lastname: Rasmussen
authors.affiliation: Department of Cardiology, Lund University Hospital, Lund.
authors.forename: S Bertil
authors.initials: SB
authors.lastname: Olsson
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Jensen
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Hamrén
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Ulf G
authors.initials: UG
authors.lastname: Eriksson
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Wåhlander
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000578:Amidines / Q000008:administration & dosage / Q000494:pharmacology*; D000925:Anticoagulants / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000097:blood / Q000188:drug therapy*; D001384:Azetidines / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D012727:Sex Characteristics; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014812:Vitamin K / Q000037:antagonists & inhibitors
chemical_list: C551586:AZD 0837; D000578:Amidines; D000925:Anticoagulants; D001384:Azetidines; D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D; D014812:Vitamin K; D013917:Thrombin
keywords: anticoagulants; atrial fibrillation; exposure-response; pharmacodynamics; pharmacokinetic; thrombin