Antithrombotic effect of LB-30057 (CI-1028), a new synthetic thrombin inhibitor, in a rabbit model of thrombosis: Comparison with inogatran

LB-30057 (CI-1028) is a novel, orally bioavailable, direct thrombin inhibit or with a Ki of 0.38 nM against human thrombin. The effects of LB-30057 on thrombus formation and hemostasis were evaluated in a veno-venous shunt mod el of thrombosis in rabbits, and compared with inogatran, another direct in hibitor of thrombin. Each compound was studied at 5 or 6 different doses wi th 5 or 6 rabbits in each group. After administration as a bolus i.v. injec tion followed by continuous infusion, both LB-30057 and inogatran dose-depe ndently inhibited thrombus formation, which was measured as an increase in time to occlusion (TTO) and a decrease in thrombus weight. Both compounds a lso improved vena caval blood flow and reduced the overall incidence of thr ombotic occlusion. LB-30057 significantly prolonged TTO from 23 +/-4 min (b efore dose) to 110 +/- 10 min at the highest dose (0.7 mg/kg+47 mug/kg/min) (p <0.001), and reduced thrombus weight from 57 +/-2 mg to 15 +/-5 mg (p < 0.001). Occlusive thrombus formed in only one of six rabbits that received the highest dose of LB-30057 (vs. 13/13 in the control group, p <0.01). At the dose that produced the maximum antithrombotic effect (0.7 mg/kg+47 mug/ kg/min), LB-30057 increased aPTT and bleeding time approximately 2-and 2.5- fold above baseline, respectively. On a gravimetric basis, LB-30057 and ino gatran displayed comparable in vivo antithrombotic efficacy. When compared to equally effective anti thrombotic doses of inogatran, LB-30057 caused le ss prolongation in aPTT, had no effect on PT, and tended to have less of ef fect on bleeding time. These results indicate that LB-30057 is an effective antithrombotic compound and it appears to have a better benefit/risk profi le than inogatran in this experimental model.