Pharmacokinetics and Effects on Fibrinolytic and Coagulation Parameters of Two Doses of Recombinant Tissue-Type Plasminogen Activator in Healthy Volunteers

M Verstraete; C A P F Su; P Tanswell; W Feuerer; D Collen

doi:10.1055/s-0038-1661592

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1986; 56(01): 001-005
DOI: 10.1055/s-0038-1661592

Original Article

Schattauer GmbH Stuttgart

Pharmacokinetics and Effects on Fibrinolytic and Coagulation Parameters of Two Doses of Recombinant Tissue-Type Plasminogen Activator in Healthy Volunteers

Authors

M Verstraete

^*The Center for Thrombosis and Vascular Research, Campus Gasthuisberg, University of Leuven, Leuven, Belgium
C A P F Su

^**The Departments of Clinical Pharmacology and Biochemistry, Dr. Karl Thomae GmbH, Biberach an der Riss, West Germany
P Tanswell

^**The Departments of Clinical Pharmacology and Biochemistry, Dr. Karl Thomae GmbH, Biberach an der Riss, West Germany
W Feuerer

^**The Departments of Clinical Pharmacology and Biochemistry, Dr. Karl Thomae GmbH, Biberach an der Riss, West Germany
D Collen

^*The Center for Thrombosis and Vascular Research, Campus Gasthuisberg, University of Leuven, Leuven, Belgium

Abstract

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Summary

Pharmacokinetics and pharmacological effects of two intravenous doses of recombinant tissue-type plasminogen activator (rt-PA) (40 and 60 mg over 90 min) were determined in healthy volunteers. Mean maximum plasma concentrations were 1080 and 1560 ng/ml respectively. The steady state level during subsequent maintenance infusion of 30 mg over 6 h was 250 ng/ml. The pharmacokinetics of rt-PA showed a bi-exponential disappearance from plasma consistent with a 2-compartment model of t_½α = 5.7 min, a t_½β = 1.3 h and a total clearance of 380 ml/min.

Mean fibrinogen levels at the end of the infusions of 40 mg or 60 mg rt-PA over 90 min, measured in thawed plasma samples collected on citrate/aprotinin, decreased to 74% and 57% of the preinfusion values respectively. Plasminogen fell to 55% and 48%, and α₂-antiplasmin to 28% and 18% of initial values. No further decrease of these parameters was observed during the infusion of 30 mg rt-PA over 6 h. Only 2% of the preinfusion fibrinogen levels could be recovered as fibrinogen-fibrin degradation products. This moderate extent of systemic fibrinogenolysis is much less than that reported for therapeutic i.v. infusions of streptokinase.

Keywords

Fibrinolysis - Tissue-type plasminogen activator - Fibrinogen - Plasminogen - Pharmacokinetics

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References

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