Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects.
OBJECTIVE
The effects of ximelagatran, an oral direct thrombin inhibitor (DTI), recombinant hirudin (r-hirudin) and enoxaparin on thrombin generation and platelet activation were studied in humans.


BACKGROUND
Recombinant hirudin (parenteral DTI) and enoxaparin (low molecular weight heparin) have been demonstrated to be clinically effective in acute coronary syndromes. Ximelagatran is currently under investigation for the prevention and treatment of thromboembolism. The shed blood model allows for the study of thrombin generation and platelet activation in humans in vivo.


METHODS
This was an open-label, parallel-group study involving 120 healthy male volunteers randomized to receive one of three oral doses of ximelagatran (15, 30 or 60 mg), r-hirudin (intravenous) or enoxaparin (subcutaneous) at doses demonstrated to be clinically effective in acute coronary syndromes, or to serve as a control. Thrombin generation (prothrombin fragment 1+2 [F1+2] and thrombin-antithrombin complex [TAT]) and platelet activation (beta-thromboglobulin [beta-TG]) biomarkers were studied using a shed blood model involving blood collection from skin incisions made using standardized bleeding time devices.


RESULTS
Oral ximelagatran, intravenous r-hirudin and subcutaneous enoxaparin rapidly and significantly (p < 0.05) decreased F1+2, TAT and beta-TG levels in shed blood, indicating inhibition of thrombin generation and platelet activation. Statistically significant concentration (melagatran, the active form of ximelagatran)-response relationships for F1+2 (p = 0.005), TAT (p = 0.005) and beta-TG (p < 0.001) levels, with IC(50)s of 0.376 (F1+2), 0.163 (TAT) and 0.115 (beta-TG) micromol/l, were detected. Melagatran showed dose-proportional pharmacokinetics with low variability. All drugs were well tolerated.


CONCLUSIONS
Oral administration of the DTI ximelagatran resulted in a rapid inhibition of both thrombin generation and platelet activation in a concentration-dependent manner using a human shed blood model. The inhibition of thrombin generation by 60 mg ximelagatran was comparable to that observed with doses of r-hirudin and enoxaparin demonstrated to be effective for the treatment of acute coronary syndromes.
Sarich
Troy C
TC
AstraZeneca LP, DCC2 W1-345, 1800 Concord Pike, Wilmington, DE 19850, USA. troy.sarich@astrazeneca.com
Wolzt
Michael
M
Eriksson
Ulf G
UG
Mattsson
Christer
C
Schmidt
Alice
A
Elg
Susanne
S
Andersson
Magnus
M
Wollbratt
Maria
M
Fager
Gunnar
G
Gustafsson
David
D
D000284:Administration, Oral; D000328:Adult; D001384:Azetidines / Q000008:administration & dosage* / Q000494:pharmacology*; D001596:Benzylamines; D004305:Dose-Response Relationship, Drug; D017984:Enoxaparin / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006629:Hirudins / Q000494:pharmacology*; D006801:Humans; D008297:Male; D015539:Platelet Activation / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000187:drug effects*
D001384:Azetidines; D001596:Benzylamines; D017984:Enoxaparin; D005343:Fibrinolytic Agents; D006629:Hirudins; D011994:Recombinant Proteins; C426686:ximelagatran; D013917:Thrombin