BIOLOGIC EFFECTS OF RECOMBINANT HIRUDIN (CGP-39393) IN HUMAN VOLUNTEERS

Objectives. The purpose of this study was to investigate the biologic efficacy and pharmacokinetics of different doses of recombinant hirudin administered in single or repeated subcutaneous injections in healthy volunteers. Background. Hirudin is a highly specific inhibitor of thrombin, the pivotal enzyme in thrombosis. Differences between hirudin and heparin in experimental animals indicate that hirudin may be a superior antithrombotic drug in humans. Methods. The biologic effect of recombinant desulfato-hirudin (CGP 39393) administered as single or repeated (every 8 h for 3 days or every 12 h for 6 days) subcutaneous injections was studied in 231 healthy human volunteers. Results. Single subcutaneous doses of 0.1, 0.2, 0.3, 0.4, 0.5 and 0.75 mg/kg body weight in 195, 8, 12, 8, 4 and 4 volunteers, respectively, prolonged the activated partial thromboplastin time in a dose-proportional fashion within the 1st 30 min, with a near-maximal effect for 3 to 4 h after the dose. The mean activated partial thromboplastin time increased to 1.48 and 1.93 times baseline values 30 min after single subcutaneous injections of 0.2 and 0.4 mg/kg of CGP 39393, respectively. There was a linear relation over a wide range between the activated partial thromboplastin time prolongation and plasma concentrations of CGP 39393. Plasma clearance was between 1.5 and 1.7 ml/min per kg. The subcutaneous administration of 0.3 and 0.5 mg recombinant hirudin three times a day for 3 days or two times a day for 6 days prolonged the activated partial thromboplastin time by 1.71 to 1.69 and 1.78 to 1.92 times baseline levels, respectively, with the preinjection values maintained in the hypocoagulable range. No prolongation of bleeding time was measured at peak plasma hirudin levels. Because thrombin and prothrombin times are not able to reflect high or low CGP 39393 concentrations, respectively, neither test is suitable for monitoring administration of this drug. Conclusions. CGP 39393 appears to be well tolerated in volunteers, even after repeated doses. The activated partial thromboplastin time test seems to be well suited to monitor the anticoagulant effect of recombinant hirudin because the dose effect is linear up to 0.5 mg/kg of subcutaneous CGP 39393. The prolongation of activated partial thromboplastin time after subcutaneous injection of CGP 39393 shows a plateau lasting for 3 h. Further studies are now required to determine the dose that will provide the best antithrombotic effect and the lowest bleeding tendency in arterial or venous thrombosis indications.