Pharmacokinetics of the novel plasminogen activator Desmodus rotundus plasminogen activator in animals and extrapolation to man

Abstract

The novel plasminogen activator Desmodus rotundus plasminogen activator (DSPA), which exhibits high fibrin specificity and thus an interesting pharmacological profile, was characterized pharmacokinetically in rats and cynomolgus monkeys after i.v. bolus administration of ¹²⁵I-labelled 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 levels. 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 rats and monkeys DSPA was characterized by long terminal half-lives of 1–2h and 5–8h with bi- or triphasically declining plasma levels. The terminal phase represented a partial area under the curve (AUC) of 42%–57% in monkeys. Total clearance accounted for 6–11 ml/min/kg and approximately 2 ml/min/kg in rats and monkeys, respectively. The volume of distribution in the central compartment was 0.5–0.1 l/kg in both species. Pharmacokinetics were linear and no sex-specific differences were observed. In both species plasma antigen and activity levels, and thus its pharmacokinetics, showed a linear correlation with a slope close to 1 over the dose range of 1–30 mg/kg. The use of ¹²⁵I-labelled protein only provided limited additional information for the early post-dose phase due to rapid iodine exchange. In terms of distribution in rats, radiolabel indicative for DSPA (i.e. until 30 min post application) was found in the highly perfused organs and tissues. By means of allometric extrapolation a total clearance of approximately 1 ml/min/kg was predicted for humans. DSPA displayed an advantageous pharmacokinetic and pharmacodynamic profile, especially due to its low total clearance, its long terminal half-life, and the complete fibrinolytic activity of antigen present in the plasma, as compared to other established protein fibrinolytics (e.g. t-PA). Animal data encourage the envisaged therapeutic dosage scheme with an i.v. bolus in humans.