Recombinant human thrombin: Demonstration of efficacy in models of surgical bleeding

Profuse bleeding can be a serious complication of many surgeries, and thrombin is widely used to achieve rapid hemostasis. Recombinant thrombin (rhThrombin) has been efficiently produced from precursor recombinant prethrombin-1 derived from cell culture. rhThrombin was shown to have the identical amino acid sequence and disulfide-bonding pattern found in native human thrombin. In vivo studies were performed to assess the efficacy of rhThrombin in surgical bleeding models. Two models of surgically induced bleeding were utilized: a rabbit partial hepatectomy model and a rat heminephrectomy model. In each model a template cut was made on the target organ, the vehicle (gauze or GelFoam®) soaked in either saline or the specified concentration of rhThrombin or bovine thrombin (b-thrombin) was applied to the wound, and time to hemostasis (TTH) was measured. In the rabbit study, either soaked gauze sponges (100, 500, 750, 1000, 2000 U/mL rhThrombin or 1930 U/mL b-thrombin) or Gelfoam® sponges (500 or 1000 U/mL rhThrombin or 500 and 1930 U/mL b-thrombin) were applied to the bleeding site. With gauze, b-thrombin and rhThrombin at ≥ 500 U/mL had significantly lower TTH than the vehicle alone. This was also seen with Gelfoam® sponges, and in addition both rhThrombin concentrations had significantly lower TTH than either of the b-thrombin concentrations. Similarly, in the rat study gauze sponges (100, 500, 1000, 2000 U/mL rhThrombin or 1930 U/mL b-thrombin) or Gelfoam® sponges (500, 1000 U/mL rhThrombin or 1930 U/mL b-thrombin) were applied. Significantly reduced TTH compared to vehicle was observed with gauze at ≥ 1000 U/mL rhThrombin and with Gelfoam® at ≥ 500 U/mL. Interestingly, with both gauze and Gelfoam®, rhThrombin at these concentrations had a reduced TTH compared to b-thrombin. Data from these models demonstrate that rhThrombin is effective in achieving hemostasis. A first in-human study has been conducted to evaluate the safety of rhThrombin and to determine a recommended dose for Phase 2 studies. No drug-related adverse events were observed. Timely hemostasis was achieved in all cases.