Dose-ranging study of the novel recombinant plasminogen activator BM 06.022 in healthy volunteers.
The novel recombinant plasminogen activator BM 06.022 consists of the kringle 2 and protease domains of human tissue-type plasminogen activator and is unglycosylated because of its expression in Escherichia coli cells. Pharmacokinetics for activity and hemostatic effects of BM 06.022 were studied in 18 healthy male volunteers after an intravenous bolus injection over 2 minutes. BM 06.022 was administered successively at doses of 0.1125, 0.55, 2.2, 3.3, 4.4, and 5.5 MU to three volunteers. Plasma fibrinogen was unchanged; effects of BM 06.022 were observed on plasminogen only at higher doses, and dose-dependent effects were seen on alpha 2-antiplasmin and fibrin D-dimers. The concentration of plasminogen and alpha 2-antiplasmin was 87% +/- 3% and 79% +/- 3%, respectively, of baseline 2 hours after injection of 5.5 MU of BM 06.022. Fibrin D-dimers were highest with 1147 +/- 380 ng/ml at 5.5 MU of BM 06.022. The area under the activity concentration-time curve (AUC) increased dose-dependently and linearly. At 5.5 MU of BM 06.022, the AUC was 313 +/- 47 IU.hr.ml-1, the total plasma clearance was 306 +/- 40 ml/min, and the half-life was 14.4 +/- 1.1 minutes.
Martin
U
U
Department of Clinical Pharmacology, Boehringer Mannheim GmbH, Mannheim, Germany.
von Möllendorff
E
E
Akpan
W
W
Kientsch-Engel
R
R
Kaufmann
B
B
Neugebauer
G
G
D000328:Adult; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D012016:Reference Values; D012044:Regression Analysis; D010959:Tissue Plasminogen Activator / Q000493:pharmacokinetics / Q000494:pharmacology*
D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; C087896:reteplase; D010959:Tissue Plasminogen Activator