title: A recombinant hirudin (IK-HIR02) in healthy volunteers. I. Effects on coagulation parameters and bleeding time.
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.
authors: International Institute of Thrombosis and Vascular Diseases, Frankfurt am Main, Germany.
authors: J F
authors: JF
authors: Schenk
authors: E
authors: E
authors: Glusa
authors: P
authors: P
authors: Radziwon
authors: A
authors: A
authors: Butti
authors: F
authors: F
authors: Markwardt
authors: H K
authors: HK
authors: Breddin
mesh_terms: D000328:Adult; D000991:Antithrombins / Q000009:adverse effects / Q000494:pharmacology*; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D006629:Hirudins / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D000991:Antithrombins; D006629:Hirudins; D011994:Recombinant Proteins; C060225:desirudin