A Recombinant Hirudin (IK-HIR02) in Healthy Volunteers

Abstract

The pharmacodynamic effects of different intravenous and subcutaneous doses of a recombinant hirudin (r-hirudin; IK-HIR02) on clotting parameters 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 aPTT in a dose-dependent manner and led to an increase in hirudin plasma levels > 6 micrograms/ml. The plasma half-life of IK-HIR02 was calculated as 1.3 h. A continuous infusion of 0.03 mg/kg/h of IK-HIR02 for 4 h significantly prolonged TT and aPTT. At the end of the hirudin infusion, a mean plasma level of 0.19 +/- 0.13 microgram/ml was measured. Single subcutaneous doses of 0.1, 0.25 and 0.5 mg/kg markedly prolonged the coagulation 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/kg. 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 microgram/ml. There was no cumulative effect after multiple injections. Bleeding time was not changed after the 4-hour intravenous infusion and after repeat subcutaneous injections of 0.3 mg/kg IK-HIR02. Bleeding time was moderately but significantly prolonged after the highest single intravenous and subcutaneous hirudin doses tested. Other than very minor local bleeding in some volunteers, IK-HIR02 was well tolerated. Biochemical blood and urine parameters did not change. In conclusion, r-hirudin (IK-HIR02) obtained by a new technique was well tolerated in healthy volunteers after single intravenous and subcutaneous injections, after repeat subcutaneous doses and during continuous intravenous infusion. Measurement of aPTT and anti-IIa activity, using a chromogenic substrate test, can be used to monitor hirudin effects if doses similar to those tested here are administered.

Pharmacokinetics of recombinant hirudin in healthy horses

“…The maximum plasma concentration of r-hirudin obtained after subcut. administration in horses (C max = 0.5 ± 0.11 mg/l) was in agreement with that of other species in which dosage and frequency of administration were similar to those used in our study (Markwardt et al 1988;Schenk et al 1996). For effective prophylaxis of venous thrombosis in man, an r-hirudin plasma concentration of 0.6 mg/l is required (Markwardt 1994;Anon 1996).…”

“…Concurrently, 2 h after subcut. administration of r-hirudin, aPTT should be prolonged 1.5-2-fold for effective prophylaxis (Bichler et al 1991;Schenk et al 1996). In our study, aPTT increased by a factor of 1.9 after 1.5 h of subcut.…”

“…administration. The observed distribution half-life of 10 and 15 mins in horses resembles the distribution phase in man (Schenk et al 1996), dogs (Marbet et al 1993;Iyer and Fareed 1996) and rats (Markwardt et al 1988). The terminal half-life of 60-80 mins was also similar to other species (man, rats, rabbits and dogs), with reported half-lives of 0.8-1.2 h (Markwardt et al 1988(Markwardt et al , 1991Bichler et al 1991;Iyer et al 1993;Schenk et al 1996).…”

“…The observed distribution half-life of 10 and 15 mins in horses resembles the distribution phase in man (Schenk et al 1996), dogs (Marbet et al 1993;Iyer and Fareed 1996) and rats (Markwardt et al 1988). The terminal half-life of 60-80 mins was also similar to other species (man, rats, rabbits and dogs), with reported half-lives of 0.8-1.2 h (Markwardt et al 1988(Markwardt et al , 1991Bichler et al 1991;Iyer et al 1993;Schenk et al 1996). Clearance (Cl tot = 1.9-2.7 ml/min/kg bwt) of r-hirudin was similar to that in man, with a reported clearance of 2.4-2.7 ml/min/kg bwt (Markwardt et al 1988(Markwardt et al , 1991Bichler et al 1991;Schenk et al 1996).…”

The Dosing and Monitoring of Argatroban for Heparin-Induced Thrombocytopenia during Extracorporeal Membrane Oxygenation: A Word of Caution

“…Both aPTT and ACT are not directly influenced by DTIs, leading to poor correlation between test results and clinical response to anticoagulation. aPTT and ACT correlation with increasing doses of DTIs is nonlinear and, while accurate at low doses, neither is accurate at increasing doses 10,11 . In our case, the use of aPTT and ACT did not correlate with clinical evidence of ECMO circuit thrombosis.…”