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.