Pharmacokinetic and hemostatic properties of the recombinant plasminogen activator bm 06.022 in healthy volunteers.
In a randomized, single-blind, placebo-controlled, cross-over Phase-I study pharmacokinetic and hemostatic properties of BM 06.022 were investigated in seven healthy, male human volunteers. The novel recombinant plasminogen activator BM 06.022 consists of the kringle 2 domain and the protease domain of human t-PA and is unglycosylated due to its expression in Escherichia coli cells. Vehicle or 6 MU (= 10.4 mg) BM 06.022 was administered as a single i.v. bolus injection of 10 ml over 2 min. BM 06.022 was well tolerated. Fibrinogen levels and clotting times remained unchanged at baseline levels after 6 MU BM 06.022; plasminogen and alpha 2-antiplasmin (collected on chloromethylketone) decreased maximally to 83 +/- 1% and 64 +/- 3%, respectively, of baseline. D-dimers and fibrinogen degradation products increased to 1,006 +/- 234 ng/ml and 555 +/- 155 ng/ml, respectively, after BM 06.022. Half-life of BM 06.022-activity was 11.2 +/- 0.4 min and of antigen was 13.9 +/- 0.7 min, followed by a terminal half-life only for antigen of 173 +/- 33 min. Plasma clearance of BM 06.022 was 371 +/- 13 ml/min for activity and 183 +/- 15 ml/min for antigen. Thus, BM 06.022 is not fibrinogenolytic at 6 MU and is a fibrinolytic agent with a longer half-life than t-PA.
Martin
U
U
Department of Pharmacology, Boehringer Mannheim GmbH, Germany.
von Möllendorff
E
E
Akpan
W
W
Kientsch-Engel
R
R
Kaufmann
B
B
Neugebauer
G
G
D000328:Adult; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics*; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D010958:Plasminogen / Q000378:metabolism*; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D012016:Reference Values; D010959:Tissue Plasminogen Activator / Q000493:pharmacokinetics* / Q000494:pharmacology; D000511:alpha-Macroglobulins / Q000378:metabolism
D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D000511:alpha-Macroglobulins; C024668:plasmin-alpha(2)-macroglobulin complex; D005340:Fibrinogen; D010958:Plasminogen; C087896:reteplase; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin