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/K(m) ratio, the intrinsic metabolic clearance, was 14-19 h-1 using a Michaelis-Menten model. The infusion regimens resulted in a approximately 15% maximum depletion of alpha 2-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.
Eppler
S
S
Department of Pharmacokinetics and Metabolism, Genentech, Inc., S. San Francisco, CA 94080, USA.
Senn
T
T
Gilkerson
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E
Modi
N B
NB
D000818:Animals; D019540:Area Under Curve; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D010960:Plasminogen Activators / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000493:pharmacokinetics*
D011994:Recombinant Proteins; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator