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.
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.
Boström
Stig L
SL
Molecular Pharmacology, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden. stig-lennart.bostrom@astrazeneca.com
Hansson
Göran F H
GF
Sarich
Troy C
TC
Wolzt
Michael
M
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
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D017984:Enoxaparin; D006629:Hirudins; D011355:Prodrugs; C426686:ximelagatran; D013917:Thrombin