Pharmacokinetics and pharmacodynamics of recombinant tissue‐type plasminogen activator following intravenous administration in rabbits: a comparison of three dosing regimens

Recombinant tissue-type plasminogen activator (rt-PA) is indicated for the treatment of acute myocardial infarction as a dose of up to 100 mg. Several clinical trials have suggested that higher patency rates can be achieved with a rapid drug administration. A study was conducted in rabbits to determine whether pharmacokinetics provides an explanation for the higher patency rates. Alteplase plasma concentration versus time profiles were compared following three dosing regimes: an accelerated 90 min, a standard 3 h, and a double-bolus regimen. The accelerated and double-bolus regimens resulted in higher initial rt-PA plasma concentrations compared to the standard regimen. No difference in the rt-PA clearance was noted between the standard and accelerated regimens. The rt-PA plasma clearance was slower following the double-bolus administration compared to either infusion regimen, suggesting a saturation of rt-PA clearance in rabbits. The estimated Vmax/Km ratio, the intrinsic metabolic clearance, was 14–19 h−1 using a Michaelis–Menten model. The infusion regimens resulted in a ∼15% maximum depletion of α2-antiplasmin levels compared to 29% for the double-bolus regimen. In summary, the higher patency following rapid rt-PA administration may be due, at least in part, to the higher rt-PA plasma concentrations. © 1998 John Wiley & Sons, Ltd.