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

Abstract

AIMS:

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: Gregory Y H Lip, Lars H Rasmussen, S Bertil Olsson, Eva Jensen, Bengt Hamrén, Ulf G Eriksson, Karin Wåhlander
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 80 Issue 6 Pg. 1362-73 (Dec 2015) ISSN: 1365-2125 [Electronic] England
• PMID: 26174611 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The British Pharmacological Society.

Chemical References

• AZD 0837
• Amidines
• Anticoagulants
• Azetidines
• Biomarkers
• Fibrin Fibrinogen Degradation Products
• fibrin fragment D
• Vitamin K
• Thrombin

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Amidines (administration & dosage, pharmacology)
• Anticoagulants (pharmacology)
• Atrial Fibrillation (blood, drug therapy)
• Azetidines (administration & dosage, pharmacology)
• Biomarkers (blood)
• Female
• Fibrin Fibrinogen Degradation Products (analysis)
• Humans
• Male
• Middle Aged
• Sex Characteristics
• Thrombin (antagonists & inhibitors, biosynthesis)
• Vitamin K (antagonists & inhibitors)