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

✍ Scribed by Stephen Eppler; Taurence Senn; Ellen Gilkerson; Nishit B. Modi

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 157 KB
• Volume: 19
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/(sici)1099-081x(199801)19:1<31::aid-bdd68>3.0.co;2-g

✦ Synopsis

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 V max /K m 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 h 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.