The antithrombotic effects of CI-1028, an orally bioavailable direct thrombin inhibitor, in a canine model of venous and arterial thrombosis

Direct thrombin inhibitors represent a new class of drug that may offer a t herapeutic alternative for the treatment and prevention of thrombembolic co nditions, especially on the venous side of the systemic circulation. CI-102 8 (PD 172524/LB30057) is a potent, highly selective inhibitor of thrombin t hat is orally bioavailable. The efficacy of this compound has been demonstr ated in animal models in which intra-venous administration was used. The ob jective of this study was to evaluate the efficacy of CI-1028 after oral ad ministration in a canine electrolytic injury model of venous and arterial t hrombosis. CI-1028 was administered via oral gavage, and animals received e ither saline or 10, 15, 20, or 30 mg/kg of drug. Fifteen minutes later, the dogs were anesthetized and a femoral artery and vein were exposed and inst rumented to induce electrolytic injury and thrombosis while continuously mo nitoring blood flow in the vessels. Maximum blood CI-1028 concentrations of 0.88 +/-0.27, 1.8 +/-0.3, 2.2 +/-0.5, and 3.2 +/-0.5 mug/mL were generally achieved 15 to 30 minutes after administering the compound in the 10-, 15- , 20-, and 30-mg/kg groups, respectively. Administration of CI-1028 increas ed the time to occlusion (TTO), the principal efficacy end point, in a dose -dependent manner in both arteries and veins. The TTO in the control group (n = 8) averaged 66 +/- 11 minutes in the arteries and 69 +/-6 minutes in t he veins. In dogs treated with 10 mg/kg (n = 8), the TTO was not significan tly different from that of the control group. In the 15-mg/kg group (n = 9) TTO averaged 140 +/- 27 minutes in the arteries (p = not significant) and 125 +/- 15 minutes (p < 0.05) in the veins. In the 20-mg/kg group (n = 8), TTO was significantly longer than controls in both types of vessels, averag ing 168 +/- 30 minutes in the arteries (p = 0.05) and 155 +/- 21 minutes (p < 0.05) in the veins. Likewise, at 30 mg/kg (n = 8) both the arterial (179 +/- 17 minutes) and venous (188 +/- 15 minutes) TTO was significantly prol onged compared with controls. Surgical blood loss and template bleeding tim es tended to increase in a dose-dependent manner but a statistically signif icant elevation was detected for template bleeding time only at the highest dose. Dramatic changes in thrombin time were detected, consistent with the CI-1028 mechanism of action. Virtually no changes were detected in prothro mbin time. Maximum activated partial thromboplastin time (aPTT) and activat ed clotting time changes were detected approximately 30 minutes after dosin g, and they were approximately twofold and fivefold baseline values, respec tively, at the highest dose. In conclusion, these results demonstrate that CI-1028 provides dose-dependent antithrombotic efficacy after oral administ ration in a canine model of venous and arterial thrombosis.