Ximelagatran--a promising new drug in thromboembolic disorders.
Ximelagatran is an oral direct thrombin inhibitor (DTI), the active form of which is melagatran. Approximately 20% of an oral ximelagatran dose becomes bioavailable as melagatran, which binds noncovalently and reversibly to both fibrin-bound and freely circulating thrombin. Oral ximelagatran dosing not only inhibits thrombin activity rapidly, competitively, and potently, but also delays and suppresses thrombin generation. In humans, oral ximelagatran exhibits anticoagulant, antiplatelet, and profibrinolytic effects, with only minor prolongation of the capillary bleeding time. Oral ximelagatran exhibits a stable and predictable pharmacokinetic profile during repeated dosing, with low intra- and inter-individual variation, and a low potential for interaction with other medications. It is excreted primarily as melagatran via the kidney, without unexpected bioaccumulation. Dosing requirements do not vary with age, gender, ethnicity, obesity, or food or alcohol intake. Clinical trials (total n>30,000) have evaluated oral ximelagatran in four indications: the prevention of venous thromboembolism (VTE, comprising deep venous thrombosis with or without and pulmonary embolism) after elective hip- or knee-replacement surgery (with approval granted by France, as the Reference Member State for the European Union); treatment and long-term secondary prevention of VTE; the prevention of stroke and other systemic embolic events associated with nonvalvular atrial fibrillation; and the prevention of cardiovascular events after an acute myocardial infarction. The results of these trials suggest that the benefit-risk profile of oral ximelagatran therapy, administered at a fixed-dose without coagulation monitoring, compares favorably with that of currently approved standard therapy.
Petersen
Palle
P
Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. pape@rh.dk
D000284:Administration, Oral; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001384:Azetidines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001596:Benzylamines; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D011355:Prodrugs; D016032:Randomized Controlled Trials as Topic; D020521:Stroke / Q000517:prevention & control; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013923:Thromboembolism / Q000517:prevention & control*; D020246:Venous Thrombosis / Q000517:prevention & control
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D011355:Prodrugs; C109573:melagatran; C426686:ximelagatran; D013917:Thrombin; D005998:Glycine