COMPARATIVE PROPERTIES OF 2 CLINICAL PREPARATIONS OF RECOMBINANT HUMAN TISSUE-TYPE PLASMINOGEN-ACTIVATOR IN PATIENTS WITH ACUTE MYOCARDIAL-INFARCTION

[摘要] The biologic properties of two clinical preparations of recombinant human tissue-type plasminogen activator were studied in 52 patients with acute myocardial infarction. The first preparation (G11021) has been used in all clinical trials reported to date, whereas the second preparation (G11035) is now produced for future clinical use. When both preparations were infused intravenously for 90 minutes at rates of 4 to 11 .mu.g/kg per min, plateau levels of the drug in plasma ranged from 0.52 .+-. 0.15 to 1.8 .+-. 0.4 .mu.g/ml and were linearly correlated with the infusion rate. However, G11035 yielded plasma levels that were approximately 35% lower than those obtained with G11021 (p < 0.025). The postinfusion disappearance rate of the drug from plasma could be described by a two compartment disposition model with the following pharmacokinetic variables. For G11021, an alpha half-life of 4.1 to 6.3 minutes, a beta half-life of 41 to 50 minutes, a central compartment volume of 3.5 to 5.4 litres, a total distribution volume of 28 to 44 liters and a plasma clearance of 450 to 640 ml/min. For G11035 these variables were 3.6 to 4.6 minutes, 39 to 53 minutes, 3.8 to 6.6 liters, 27 to 40 litres and 520 to 1,000 ml/min, respectively, indicating that G11035 is cleared more rapidly from the circulation. G11021 at 4 .mu.g/kg per min and G11035 at 7 .mu.g/kg per min did not effectively produce thrombolysis. A coronary reperfusion rate of 81% (13 of 16 patients) was obtained with 5.3 .mu.g/kg per min of G11021 and a rate of 86% (6 of 7 patients) was obtained with 9.4 .mu.g/kg per min of G11035. At these doses, the plasma fibrinogen level decreased to 69 .+-. 10 (mean .+-. SEM) and 85 .+-. 12% of baseline, respectively. A maintenance infusion of G11021 at 2 .mu.g/kg per min for 4 hours and of G11035 at 3.3 .mu.g/kg per min was given to nine patients each, resulting in plateau levels in plasma of 0.45 .mu.g/ml, which effectively prevented coronary reocclusion but was associated with a moderate (approximately 20%) additional fibrinogen breakdown. Thus, G11035 produced for future clinical use requires a 25 to 50% higher infusion rate to yield similar plasma drug levels and thrombolytic efficacy but causes less fibrinogen breakdown compared with the previously used G11021.

[发布日期] 1987-03-01