The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a mini-review☆
Section snippets
Inhibition of thrombin
Melagatran is a potent competitive inhibitor of human α-thrombin with an inhibition constant (Ki) of 0.002 μmol/l [13]. In vitro studies have shown that melagatran effectively inhibits both thrombin generation [14] and thrombin activity [13]. Both effects have also been demonstrated with ximelagatran in healthy volunteers [15], [16]. Melagatran's inhibition of the action of thrombin is demonstrated by its prolongation of plasma coagulation as measured by PT as well as thrombin time and
The pharmacokinetic properties of ximelagatran and melagatran
Although melagatran has all the pharmacodynamic properties required of a new antithrombotic agent, low oral bioavailability (approximately 5% [48]) precludes it from being administered orally. Consequently, the oral DTI, ximelagatran, of which melagatran is its active form, was developed, with the rationale of finding an alternative way of delivering melagatran by the oral route (Table 1). Ximelagatran was derived from melagatran by ethylation of the carboxylic acid group and hydroxylation of
Conclusions
Ximelagatran is currently undergoing full-scale clinical evaluation. It is the first new oral anticoagulant in advanced clinical development for more than half a century. Ximelagatran has several pharmacodynamic and pharmacokinetic advantages over warfarin, including a shallower dose–response curve, and consequently, a wider therapeutic index between anticoagulant effect and bleeding, a rapid onset of action, a low potential for drug–drug interactions, and no food–drug interactions. Together
Acknowledgements
The discovery and documentation of ximelagatran and melagatran are the result of teamwork. Many thanks to all members, past and present, of the highly committed multidisciplinary teams, for their hard and dedicated work over a long period of time.
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Proceedings from an AstraZeneca-sponsored symposium, entitled “Oral Direct Thrombin Inhibition: Changing Thrombosis Management”, at the XVIII Congress of the International Society on Thrombosis and Haemostasis, Paris, France, 7 July 2001.