title: 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.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  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.
authors.affiliation: Molecular Pharmacology, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden. stig-lennart.bostrom@astrazeneca.com
authors.forename: Stig L
authors.initials: SL
authors.lastname: Boström
authors.forename: Göran F H
authors.initials: GF
authors.lastname: Hansson
authors.forename: Troy C
authors.initials: TC
authors.lastname: Sarich
authors.forename: Michael
authors.initials: M
authors.lastname: Wolzt
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D019540:Area Under Curve; D001384:Azetidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D001596:Benzylamines; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D017984:Enoxaparin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D006629:Hirudins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D012449:Safety; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013997:Time Factors
chemical_list: D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D017984:Enoxaparin; D006629:Hirudins; D011355:Prodrugs; C426686:ximelagatran; D013917:Thrombin