A RECOMBINANT HIRUDIN (IK-HIRO2) IN HEALTHY-VOLUNTEERS .1. EFFECTS ONCOAGULATION PARAMETERS AND BLEEDING-TIME

The pharmacodynamic effects of different intravenous and subcutaneous doses of a recombinant hirudin (r-hirudin; IK-HIR02) on clotting param eters and bleeding time were investigated in 24 healthy volunteers in a bicenter study. Single intravenous bolus injections of 0.1, 0.2 and 0.3 mg/ kg IK-HIR02 caused a prolongation of thrombin time (TT) and aP TT in a dose-dependent manner and led to an increase in hirudin plasma levels > 6 mu g/ml. The plasma half-life of IK-HIR02 was calculated a s 1.3 h. A continuous infusion of 0.03 mg/kg/h of IK-HIR02 for 4 h sig nificantly prolonged TT and aPTT. At the end of tile hirudin infusion, a mean plasma level of 0.19 +/- 0.13 mu g/ml was measured. Single sub cutaneous doses of 0.1, 0.25 and 0.5 mg/kg markedly prolonged the coag ulation tests. The highest increase in hirudin plasma levels was found 2 h after injection. At this time the aPTT was doubled after 0.5 mg/k g. After repeat subcutaneous injections of 0.3 mg/kg b.i.d., aPTT was doubled, and TT increased to about 200 s, 2 h after the injections. At this time the mean plasma level was 0.5-0.6 0.6 mu g/ml. There was no cumulative effect after multiple injections. Bleeding time was not ch anged after the 4-hour intravenous infusion and after repeat subcutane ous injections of 0.3 mg/kg IK-HIR02. Bleeding time was moderately but significantly prolonged after the highest single intravenous and subc utaneous hirudin doses tested. Other than very minor local bleeding in some volunteers, IK-HIR02 was well tolerated. Biochemical blood and u rine parameters did not change. In conclusion, r-hirudin (IK-HIR02) ob tained by a new technique was well tolerated in healthy volunteers aft er single intravenous and subcutaneous injections, after repeat subcut aneous doses and during continuous intravenous infusion. Measurement o f aPTT and anti-IIa activity, using a chromogenic substrate test, can be used to monitor hirudin effects if doses similar to those tested he re are administered.