DOUBLE-BOLUS VERSUS SINGLE-BOLUS THROMBOLYSIS WITH RETEPLASE FOR ACUTE-MYOCARDIAL-INFARCTION - A PHARMACOKINETIC AND PHARMACODYNAMIC STUDY

Reteplase, a K2P deletion mutant of tissue plasminogen activator, is a novel recombinant thrombolytic agent, designed primarily for bolus th rombolysis in acute myocardial infarction. To avoid early reocclusion, which had been substantial after single-bolus therapy, the concept of double-bolus thrombolysis was developed and evaluated in recently pub lished clinical trials. In this study, the pharmacokinetic profiles of double-bolus thrombolysis with 10 + 10 or 10 + 5 units (U) of retepla se at 30 min intervals were compared to that of a single 15 U bolus an d the relative impacts on the hemostatic system were investigated. By splitting the dose of 15 U of reteplase in boluses of 10 + 5 U, median plasma antigen and activity levels above 700 ng/ml and 250 aU/ml (act ivity units) were prolonged by 1.5 min; all other pharmacokinetic prop erties and the pharmacodynamic variables investigated were similar in the 15 and 10 + 5 U groups. By doubling the dose of the second bolus t o 10 U, a further prolongation of 45 min and 35 min was observed; medi an reteplase activity peaks were distinctly higher than relative antig en peaks after the second 10 U bolus, probably indicating that residua l inhibitory activity against the plasminogen activator was overcome b y the high activator dose, corresponding well with the higher patency rates found for this dosage in earlier clinical studies. In the 10 + 1 0 U group, more distinct alterations in hemostatic variables were obse rved, with increased fibrinogen consumption and split-product producti on resulting in a more pronounced fibrinolytic state. In accordance wi th previous studies, we found plasma alpha- and beta-half-lives of ret eplase to be 4 and 19 times longer than those of alteplase, No deaths, strokes, major bleedings or overt allergic reactions were observed. A s an important limitation of our study, it has to be stated that our o wn clinical findings, particularly the patency rates, disharmonize wit h expected results and results from larger trials investigating clinic al end-points. Reasons for this could have included the small sample s ize of our study, relatively long times to treatment and an increased degree of thrombin activation prior to thrombolysis in the groups with low patency rates.