The pharmacokinetics of recombinant double-chain t-PA (duteplase): effects of bolus injection, infusions, and administration by weight in patients with myocardial infarction.

The current mode of administration of recombinant tissue-type plasminogen activator (rt-PA) in acute myocardial infarction is rather complex, although the rationale for the different components of this scheme is not clearly established. We compared pharmacokinetics of a continuous infusion of 38.5 MU of Burroughs Wellcome t-PA (duteplase) over 90 minutes in nine patients (phase I) with a scheme including a 0.04 MU/kg bolus, a 60-minute 0.36 MU/kg lytic infusion and a 180-minute 0.21 MU/kg maintenance infusion in 15 patients with acute myocardial infarction (Phase II). t-PA activity and antigen were fitted in a one-compartment model from which model-dependent and model-independent parameters were derived. Clearance of t-PA activity was 1020 +/- 465 (mean +/- SD) ml/min in phase I and 1359 +/- 590 ml/min in phase II. Clearance of t-PA antigen was 666 +/- 230 ml/min in phase I and 704 +/- 199 ml/min in phase II. Clearance of activity was significantly (p less than 0.01) higher than of antigen. Clearance and steady-state plasma levels showed a large interindividual variability (coefficient of variation, 56.4%), but this was significantly reduced by dosing by weight (coefficient of variation, 28.9%; p = 0.031). A 10% bolus in phase II shortened the time to reach 75% and 90% of the steady-state plasma level by 4 and 5 minutes, respectively, not significantly different from phase I. A simulation study showed that a bolus should be approximately 15% of the lytic dose to achieve a maximal level in the shortest period.