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

Abstract

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 t1/2 alpha = 5.7 min, a t1/2 beta = 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 alpha 2-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.