Elsevier

Thrombosis Research

Volume 109, Supplement, 15 July 2003, Pages S9-S15
Thrombosis Research

The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a mini-review

https://doi.org/10.1016/S0049-3848(03)00249-4Get rights and content

Abstract

Ximelagatran (Exanta™, AstraZeneca) is a novel, oral direct thrombin inhibitor (oral DTI) that is rapidly converted to melagatran, its active form, following absorption. Melagatran has been shown to be a potent, rapidly binding, competitive inhibitor of human α-thrombin that inhibits both thrombin activity and generation. Melagatran also effectively inhibits both free and clot-bound thrombin. Melagatran has a wide therapeutic interval that enables it to be administered safely across a wide range of doses with no increased risk of bleeding, in contrast with warfarin whose narrow therapeutic window necessitates monitoring of its pharmacodynamic effect. Although melagatran has all the pharmacodynamic properties required of a new antithrombotic agent, low oral bioavailability that is even further reduced by the concomitant intake of food precludes its development as an oral agent. It was this that propelled the development of its prodrug, ximelagatran, which is 170 times more lipophilic than melagatran and uncharged at intestinal pH. Ximelagatran is therefore much better than melagatran at penetrating the gastrointestinal barrier and, as a consequence, has sufficient bioavailability (20%) for oral administration. Moreover, its pharmacokinetic properties following oral administration are stable and reproducible, with no food interactions and a low potential for drug–drug interactions. These properties allow ximelagatran to be administered twice daily according to a fixed dose regimen without coagulation monitoring. As a consequence of its favourable pharmacokinetic and pharmacodynamic properties, ximelagatran is currently undergoing full-scale clinical development for the prophylaxis and treatment of thromboembolic disorders.

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.

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