PHARMACOKINETICS OF THE NOVEL PLASMINOGEN-ACTIVATOR DESMODUS-ROTUNDUSPLASMINOGEN-ACTIVATOR IN ANIMALS AND EXTRAPOLATION TO MAN

The novel plasminogen activator Desmodus rotundus plasminogen activato r (DSPA), which exhibits high fibrin specificity and thus an interesti ng pharmacological profile, was characterized pharmacokinetically in r ats and cynomolgus monkeys after i.v. bolus administration of I-125-la belled protein. Furthermore, several toxicokinetic studies with single or repeated administration of unlabelled DSPA were monitored by ELISA and fibrin clot lysis assay (FCLA) to measure antigen and activity le vels. The dose range used in both species was 1 to 30 mg/kg. Data were used to describe the pharmacokinetic profile of DSPA in animals. In r ats and monkeys DSPA was characterized by long terminal half-lives of 1-2 h and 5-8 h with bi- or triphasically declining plasma levels. The terminal phase represented a partial area under the curve (AUG) of 42 %-57% in monkeys. Total clearance accounted for 6-11 ml/min/kg and app roximately 2 ml/min/kg in rats and monkeys, respectively. The volume o f distribution in the central compartment was 0.5-0.1 I/kg in both spe cies. Pharmacokinetics were linear and no sex-specific differences wer e observed. In both species plasma antigen and activity levels, and th us its pharmacokinetics, showed a linear correlation with a slope clos e to I over the dose range of 1-30 mg/kg. The use of 125I-labelled pro tein only provided limited additional information for the early post-d ose phase due to rapid iodine exchange. In terms of distribution in ra ts, radiolabel indicative for DSPA (i.e. until 30 min post application ) was found in the highly perfused organs and tissues. By means of all ometric extrapolation a total clearance of approximately 1 ml/min/kg w as predicted for humans. DSPA displayed an advantageous pharmacokineti c and pharmacodynamic profile, especially due to its low total clearan ce, its long terminal half-life, and the complete fibrinolytic activit y of antigen present in the plasma, as compared to other established p rotein fibrinolytics (e.g. t-PA). Animal data encourage the envisaged therapeutic dosage scheme with an i.v. bolus in humans.