BACKGROUND:BB-10153 is an engineered variant of human plasminogen that is activated to plasmin by thrombin. Thrombus-selective induction of reperfusion and prevention of reocclusion have been demonstrated following bolus administration in animal models of thrombosis. OBJECTIVE AND METHODS: The objective of the study was to examine the pharmacokinetics and pharmacodynamics of BB-10153 administered as an intravenous bolus to healthy male human volunteers. Cohorts of four were dosed with BB-10153 (n = 3) or placebo (n = 1). In total, placebo was received by eight volunteers and 0.08, 0.2, 0.6, 1.2, 1.8, 2.4, 3.6 and 4.8 mg kg(-1) BB-10153 by three volunteers each. RESULTS: There was a linear relationship between AUC/Cmax and dose. The half-life of BB-10153 was approximately 3-4 h and all the BB-10153 in the circulation retained the ability to be activated by thrombin. There was a dose-related increase in plasma fibrin D-dimers. Ex vivo plasma clot lysis was observed at doses of 3.6 and 4.8 mg kg(-1), whereas lysis of clots formed from euglobulin-fractionated plasma was first evident at 0.6 mg kg(-1) and activity increased with dose. This activity decreased with time in line with the half-life. BB-10153 had no effect on plasma alpha2-antiplasmin or fibrinogen levels, coagulation assays or bleeding time. An increase in plasminogen was observed as BB-10153 was detected by the enzyme-linked immunosorbent assay (ELISA) for human plasminogen. CONCLUSIONS:BB-10153 was well tolerated and had a 3-4-h plasma half-life. Fibrinolytic activity was demonstrated by dose-related ex vivo clot lysis and in vivo production of fibrin D-dimers. These effects were not accompanied by consumption of alpha2-antiplasmin or fibrinogen.
RCT Entities:
BACKGROUND: BB-10153 is an engineered variant of human plasminogen that is activated to plasmin by thrombin. Thrombus-selective induction of reperfusion and prevention of reocclusion have been demonstrated following bolus administration in animal models of thrombosis. OBJECTIVE AND METHODS: The objective of the study was to examine the pharmacokinetics and pharmacodynamics of BB-10153 administered as an intravenous bolus to healthy male human volunteers. Cohorts of four were dosed with BB-10153 (n = 3) or placebo (n = 1). In total, placebo was received by eight volunteers and 0.08, 0.2, 0.6, 1.2, 1.8, 2.4, 3.6 and 4.8 mg kg(-1) BB-10153 by three volunteers each. RESULTS: There was a linear relationship between AUC/Cmax and dose. The half-life of BB-10153 was approximately 3-4 h and all the BB-10153 in the circulation retained the ability to be activated by thrombin. There was a dose-related increase in plasma fibrin D-dimers. Ex vivo plasma clot lysis was observed at doses of 3.6 and 4.8 mg kg(-1), whereas lysis of clots formed from euglobulin-fractionated plasma was first evident at 0.6 mg kg(-1) and activity increased with dose. This activity decreased with time in line with the half-life. BB-10153 had no effect on plasma alpha2-antiplasmin or fibrinogen levels, coagulation assays or bleeding time. An increase in plasminogen was observed as BB-10153 was detected by the enzyme-linked immunosorbent assay (ELISA) for human plasminogen. CONCLUSIONS: BB-10153 was well tolerated and had a 3-4-h plasma half-life. Fibrinolytic activity was demonstrated by dose-related ex vivo clot lysis and in vivo production of fibrin D-dimers. These effects were not accompanied by consumption of alpha2-antiplasmin or fibrinogen.
Authors: C Michael Gibson; Cafer Zorkun; Peter Molhoek; Krzysztof Zmudka; Mark Greenberg; Hiltrud Mueller; Jan Wesdorp; Hans Louwerenburg; Alan Niederman; Jaap Westenburg; Mahesh Bikkina; John Batty; Jobst de Winter; Sabina A Murphy; Carolyn H McCabe Journal: J Thromb Thrombolysis Date: 2006-08 Impact factor: 2.300