Pharmacokinetics and anticoagulant effect of the direct thrombin inhibitor melagatran following subcutaneous administration to healthy young men.
The pharmacokinetic dose linearity and reproducibility, the effects on ex-vivo coagulation time assays and bleeding time, and tolerability of the direct thrombin inhibitor melagatran following subcutaneous (s.c.) dosing were investigated in two open-label studies in healthy males: (i). a dose-escalation study in which subjects received single s.c. doses of melagatran (0.1-5 mg); and (ii). a repeated-dosing study in which 3 mg s.c. melagatran was administered at 12-h intervals for 4 days. In both studies, melagatran was rapidly absorbed with maximum plasma concentrations (C(max)) observed about 0.5 h post dosing. The half-life of melagatran was about 2 h. The area under the melagatran plasma concentration versus time curve increased linearly with dose. No time dependency in the area under the curve or Cmax was observed over 4 days of twice-daily dosing. The variability in pharmacokinetic parameters was low and the bioavailability of melagatran appeared to be complete. There was a steep and linear prolongation of thrombin time, a non-linear prolongation of both activated partial thromboplastin time and activated coagulation time, and a decrease in prothrombin complex activity with increasing melagatran plasma concentration. Only moderate increases in capillary bleeding time were observed with s.c. doses up to 5 mg melagatran. Melagatran was well tolerated after s.c. injection, with good local tolerability at the injection site.
D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D001384:Azetidines; D001596:Benzylamines; D001682:Biological Availability; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D010599:Pharmacokinetics; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; C109573:melagatran; D013917:Thrombin; D005998:Glycine