Effects of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and dalteparin on the endogenous thrombin potential in venous blood from healthy male subjects.
The effect of the oral direct thrombin inhibitor ximelagatran and its active form, melagatran, on thrombin generation was investigated in vitro and ex vivo using a thrombin generation assay. In-vitro thrombin generation was triggered in human platelet-poor plasma by the addition of tissue factor, and the endogenous thrombin potential (ETP) was measured. The ETP IC(50) values for melagatran and the low-molecular-weight heparin dalteparin were 0.44 micromol/l and 0.06 IU/ml, respectively. In contrast to dalteparin, melagatran increased the time-to-thrombin peak in a concentration-dependent manner. ETP was also studied ex vivo in platelet-poor plasma collected from healthy male subjects (n = 54) at pre-dose and 2 h post-dose, with ximelagatran (60 mg) orally, dalteparin (120 IU/kg) subcutaneously, or control (water) orally. After ximelagatran or dalteparin administration, the time-to-thrombin peak was prolonged by 41 and 95%, and the ETP was decreased by 61 and 77%, respectively. Thus, melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, efficiently delays and inhibits the generation of thrombin in plasma both in vitro and ex vivo.
Boström
Stig L
SL
AstraZeneca R&D, Mölndal, Sweden. stig-lennart.bostrom@astrazeneca.com
Hansson
Göran F
GF
Kjaer
Magnus
M
Sarich
Troy C
TC
D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology*; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D001596:Benzylamines; D017985:Dalteparin / Q000008:administration & dosage / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007279:Injections, Subcutaneous; D008297:Male; D012016:Reference Values; D013917:Thrombin / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013997:Time Factors; D014680:Veins
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D065427:Factor Xa Inhibitors; C109573:melagatran; C426686:ximelagatran; D013917:Thrombin; D017985:Dalteparin; D005998:Glycine