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.
Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
R W
RW
Koster
A F
AF
Cohen
C
C
Kluft
F J
FJ
Kasper
P A
PA
van der Wouw
B C
BC
Weatherley
D000368:Aged; D001835:Body Weight; D004341:Drug Evaluation; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; C068645:duteplase