ABSTRACT
An anticoagulant at present undergoing investigation for possible clinical use. It is a dipeptide mimetic of the region of fibrinopeptide A that interacts with the active site on thrombin and hence is a direct thrombin inhibitor. This is unlike heparin or warfarin, which are indirect inhibitors acting through antithrombin (heparin) or an inhibitor of coagulation protein production (warfarin). As a direct thrombin inhibitor, it can inhibit both free and clot-bound thrombin. Theoretically, this produces more-effective anticoagulation by inhibition of clot-bound thrombin, believed to be responsible for thrombus propagation. Ximelagatran is a prodrug of the active metabolite melagatran and can be administered orally. After absorption, it is hydrolyzed to melagatran. Ximelagatran’s oral bioavailability is approximately 18 to 24%, resulting in low interindividual variability in resultant melagatran plasma levels. It has been demonstrated to have a relatively wide therapeutic window in terms of bleeding and antithrombotic effect compared with warfarin. As a result, it does not require monitoring and can be administered in a fixed dosing regime. There is an apparent lack of drug-drug and drug-food interactions with ximelagatran, which would offer a major clinical and practical advantage over warfarin. Clinical studies have demonstrated ximelagatran to be comparable in efficacy to warfarin and lowmolecular-weight heparins (LMWH) for prophylaxis of venous thromboembolism; comparable to warfarin for stroke prevention in the setting of atrial fibrillation; and, when combined with aspirin, possibly more effective than aspirin alone at preventing major adverse cardiovascular events in patients with a recent myocardial infarction. Adverse effects with ximelagatran primarily involve bleeding complications, which appear comparable to those occurring with standard anticoagulant treatment (i.e., warfarin and LMWH). Ximelagatran has also been demonstrated to cause transient increases in liver enzymes, the significance of which is unclear. Ximelagatran currently remains an investigational drug.
