Low-dose infusion of recombinant tissue-type plasminogen activator in healthy volunteers to investigate the biodistribution of t-PA in the early phase of infusion

Earlier observations suggested deviations from expected pharmacokinetics of recombinant tissue-type plasminogen activator (rt-PA) in the early phase of a low-dose infusion. A study with two low-dose intravenous infusions of rt-PA was performed on 10 healthy volunteers in an open randomized two-way crossover design. Doses of 150 and 300 jig rt-PA were administered over 40 min and blood samples were collected to measure tissue-type plasminogen activator (t-PA) antigen concentrations. Pre- and post-infusion data were used to predict a concentration profile during infusion without t-PA binding and these values were compared to actual measurements with the t-PA binding. The difference between the observed and predicted area under the concentration curve over the duration of infusion was 49ng'min/ml (95% confidence interval (C): +21, +78) for the 150n.g infusion and 29ng'min/ml (CI: -4, +61) for the 300 (ig infusion. The average amount of rt-PA that was apparently missing was 28 μg (CI: +12, +44) after the 150 μg infusion and 21 μg (CI: -9, +52) after the 300 μg infusion. These results indicate a distribution of t-PA over one or more compartments which might include or be the endothelium. Low-dose infusions could be valuable in defining this distribution in various patient groups and might be relevant in relation to the measurement of endothelial dysfunction.