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CLINICAL STUDY: ANTITHROMBOTIC THERAPY

Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects

Troy C. Sarich, PhD^*,*, Michael Wolzt, MD, Ulf G. Eriksson, PhD, Christer Mattsson, PhD, Alice Schmidt, MD, Susanne Elg, MSc, Magnus Andersson, MSc, Maria Wollbratt, MSc, Gunnar Fager, MD, PhD and David Gustafsson, MD, PhD

^* AstraZeneca LP, Wilmington, Delaware, USA
Department of Clinical Pharmacology, Allgemeines Krankenhaus Wien, University of Vienna, Vienna, Austria
AstraZeneca R&D Mölndal, Mölndal, Sweden

Manuscript received April 29, 2002; revised manuscript received October 4, 2002, accepted November 1, 2002.

^* Reprint requests and correspondence: Dr. Troy C. Sarich, AstraZeneca LP, DCC2 W1-345, 1800 Concord Pike, Wilmington, Delaware 19850, USA.
troy.sarich{at}astrazeneca.com

OBJECTIVES: The effects of ximelagatran, an oral direct thrombin inhibitor (DTI), recombinant hirudin (r-hirudin) and enoxaparin on thrombin generation and platelet activation were studied in humans.

BACKGROUND: Recombinant hirudin (parenteral DTI) and enoxaparin (low molecular weight heparin) have been demonstrated to be clinically effective in acute coronary syndromes. Ximelagatran is currently under investigation for the prevention and treatment of thromboembolism. The shed blood model allows for the study of thrombin generation and platelet activation in humans in vivo.

METHODS: This was an open-label, parallel-group study involving 120 healthy male volunteers randomized to receive one of three oral doses of ximelagatran (15, 30 or 60 mg), r-hirudin (intravenous) or enoxaparin (subcutaneous) at doses demonstrated to be clinically effective in acute coronary syndromes, or to serve as a control. Thrombin generation (prothrombin fragment 1+2 [F1+2] and thrombin-antithrombin complex [TAT]) and platelet activation (ß-thromboglobulin [ß-TG]) biomarkers were studied using a shed blood model involving blood collection from skin incisions made using standardized bleeding time devices.

RESULTS: Oral ximelagatran, intravenous r-hirudin and subcutaneous enoxaparin rapidly and significantly (p < 0.05) decreased F1+2, TAT and ß-TG levels in shed blood, indicating inhibition of thrombin generation and platelet activation. Statistically significant concentration (melagatran, the active form of ximelagatran)-response relationships for F1+2 (p = 0.005), TAT (p = 0.005) and ß-TG (p < 0.001) levels, with IC₅₀s of 0.376 (F1+2), 0.163 (TAT) and 0.115 (ß-TG) µmol/l, were detected. Melagatran showed dose-proportional pharmacokinetics with low variability. All drugs were well tolerated.

CONCLUSIONS: Oral administration of the DTI ximelagatran resulted in a rapid inhibition of both thrombin generation and platelet activation in a concentration-dependent manner using a human shed blood model. The inhibition of thrombin generation by 60 mg ximelagatran was comparable to that observed with doses of r-hirudin and enoxaparin demonstrated to be effective for the treatment of acute coronary syndromes.

Abbreviations and Acronyms   aPTT   activated partial thromboplastin time   DTI   direct thrombin inhibitor   ESSENCE   Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events   F1+2   prothrombin fragment 1+2   IV   intravenous   LMWH   low molecular weight heparin   OASIS   Organization to Assess Strategies for Ischemic Syndromes   r-hirudin   recombinant hirudin   SC   subcutaneous   TAT   thrombin-antithrombin complex   ß-TG   ß-thromboglobulin

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