Saruplase, or unglycosylated,
single-chain urokinase-type plasminogen activator (scu-PA) selectively activates
fibrin-bound
plasminogen, and is subsequently converted to its two-chain derivative tcu-PA (
urokinase) by
plasmin. The efficacy of a 20 mg IV bolus followed by an infusion of 60 mg over 1 hour (standard regimen) has been demonstrated in acute
myocardial infarction (AMI). The Bolus Administration of
Saruplase in Europe (BASE) study compared the efficacy of standard
therapy, single bolus (80 mg), and split bolus (2 x 40 mg at 30-minute intervals) in AMI. In a substudy of BASE, the pharmacokinetics of total
u-PA activity (amidolytic activity after
plasmin treatment), high molecular weight (HMW)
u-PA antigen, and tcu-PA activity were compared in patients receiving standard
therapy (n = 4), single bolus (n = 4), or split bolus (n = 5). Total
u-PA activity and HMW
u-PA antigen were similar. The maximum concentration (C(max,), mean +/- SD) of total
u-PA activity was 2.2 +/- 0.3 microg/mL after standard
therapy, 16.3 +/- 3.9 microg/mL after single bolus, and 8.2 +/- 1.6 ug/mL after split bolus. The area under the concentration versus time curve (AUC) values of total
u-PA activity were 1.7 +/- 0.1 microg/mL*h (standard
therapy), 4.0 +/- 0.9 microg/mL*h (bolus), and 3.0 +/- 0.7 microg/mL*h (split bolus). The dominant initial half-lives (t(1/2) alpha) were 7.1 +/- 1.1 minutes (standard), 8.8 +/- 0.8 minutes (bolus), and 5.1 +/- 2.1 minutes (split bolus). Maximum plasma concentrations of of tcu-PA activity were observed at 5.2 +/- 7 minutes (standard), 21 +/- 10 minutes (bolus), and 42 +/- 2 minutes (split bolus). C(max) was lowest after standard
therapy (0.6 +/- 0.3 microg/mL), highest after bolus (4.2 +/- 2.2 microg/mL), and approximately twice as high as standard
therapy after split bolus (1. 3 +/- 0.8 microg/mL). After standard
therapy the mean
fibrinogen concentration decreased gradually from approximately 300 mg/dL to 70 mg/dL at 90 and 120 minutes. After a single bolus the
fibrinogen concentration decreased below the limit of quantification within 30 minutes and remained there for at least 120 minutes. Directly after the second 40 mg dose of the split bolus, the
fibrinogen levels had an accelerated and more pronounced decrease to approximately 65 mg/dL at 90 and 120 minutes. A single bolus results in very high early total
u-PA activity, which accelerates the appearance of tcu-PA activity and
fibrinogen consumption. The pharmacokinetics and
hemostatic effects of the split-bolus regimen are more comparable with those of standard
therapy.