The inhibitory effect of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, compared with enoxaparin and r-hirudin on ex vivo thrombin generation in human plasma

INTRODUCTION: The effect of the oral direct thrombin inhibitor (DTI) ximelagatran (Exanta, AstraZeneca) on the endogenous thrombin potential (ETP) of activated plasma was investigated ex vivo using a thrombin generation assay and compared with recombinant (r)-hirudin and enoxaparin. MATERIALS AND METHODS: 120 healthy male volunteers were randomized to one of six treatment groups (n=20 in each): oral ximelagatran (15, 30, or 60 mg), intravenous r-hirudin (0.4 mg/kg bolus, 0.15 mg/kg/h infusion for 2 h, followed by 0.075 mg/kg/h infusion for 2 h), subcutaneous enoxaparin (100 IU/kg), or control (tap water administered orally). Venous blood was collected predose and at 2, 4, and 10 h postdosing. Thrombin generation was triggered by the addition of tissue factor to platelet-poor plasma, and the ETP and time to peak thrombin generation were measured. RESULTS AND CONCLUSIONS: A significant and dose-dependent reduction in ETP was observed 2 and 4 h after the administration of ximelagatran 30 mg (70.3% of predose, 95% confidence intervals 63.0-78.5, P<0.0001 at 2 h) and 60 mg (49.8%, 43.2-57.4, P<0.0001 at 2 h), r-hirudin (19.5%, 10.1-37.6, P<0.0001 at 2 h), and enoxaparin (34.2%, 21.4-54.7, P<0.0001 at 2 h). Ximelagatran (30 mg, 3.79 min, 3.52-4.08 at 2 h), r-hirudin (6.23 min, 4.93-7.86 at 2 h), and enoxaparin (4.68 min, 3.30-6.64 at 2 h) also delayed the lag phase before the thrombin generation burst compared to placebo (2.92 min, 2.71-3.25 at 2 h). The oral DTI ximelagatran, in its active form melagatran, is a potent thrombin inhibitor that efficiently decreases ETP and delays the generation of thrombin in plasma in this ex vivo model.