Ximelagatran: an orally active direct thrombin inhibitor.
OBJECTIVE
The chemistry, pharmacology, pharmacokinetics, clinical efficacy, dosage and administration, contraindications, and adverse effects of ximelagatran are reviewed.


CONCLUSIONS
Ximelagatran is the first orally active direct thrombin inhibitor to be tested in Phase III clinical trials. After oral administration, ximelagatran is rapidly converted to its active metabolite, melagatran. Melagatran (after oral ximelagatran administration) predictably inhibits thrombin function without need for routine anticoagulation monitoring. Melagatran effectively inhibits both free and clot-bound thrombin-a potential pharmacodynamic advantage over heparin products. Melagatran has a half-life of 2.4-4.6 hours, necessitating twice-daily administration. Melagatran is primarily eliminated by the kidneys and has not been studied clinically in patients with severe renal failure. Ximelagatran has undergone 10 Phase III trials (6 for prophylaxis of venous thromboembolism [VTE] due to orthopedic surgery, 1 for initial treatment of VTE, 1 for long-term prevention of VTE recurrence, and 2 for stroke prophylaxis due to atrial fibrillation). Results were generally positive. AstraZeneca applied in December 2003 for marketing approval of ximelagatran for prevention of VTE after total knee replacement surgery, long-term prevention of VTE recurrence after standard therapy, and stroke prevention due to atrial fibrillation. FDA denied approval of ximelagatran for all indications, mainly because of increased rates of coronary artery disease events in ximelagatran recipients in some studies and the possibility of hepatic failure when the medication is used for long-term therapy.


CONCLUSIONS
Ximelagatran has shown promise as a possible alternative to warfarin and other anticoagulants but will require further study to ensure its safety.
University of Minnesota College of Pharmacy/Saint Mary's Medical Center, 344 Kirby Plaza, 1208 Kirby Drive, Duluth, MN 55812, USA. mgulseth@umn.edu
Michael P
MP
Gulseth
D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000150:complications; D001384:Azetidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001596:Benzylamines; D001682:Biological Availability; D017326:Clinical Trials, Phase III as Topic; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D008657:Metabolic Clearance Rate; D020521:Stroke / Q000209:etiology / Q000517:prevention & control; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013923:Thromboembolism / Q000517:prevention & control; D020246:Venous Thrombosis / Q000517:prevention & control; D014859:Warfarin / Q000009:adverse effects / Q000627:therapeutic use
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; C426686:ximelagatran; D014859:Warfarin; D013917:Thrombin