PHARMACOKINETICS AND PHARMACODYNAMICS OF TP-9201, A GPIIBIIIA ANTAGONIST, ADMINISTERED IN COMBINATION WITH RECOMBINANT TISSUE-TYPE PLASMINOGEN-ACTIVATOR, HEPARIN, AND ASPIRIN IN BEAGLES

The effect of heparin, aspirin, and recombinant tissue-type plasminoge n activator (rt-PA) on TP-9201 pharmacokinetics and pharmacodynamics w as investigated in beagles. Animals received TP-9201, an Arginine-Glyc ine-Aspartic acid (RGD)-containing synthetic peptide glycoprotein (gp) IIbIIIa antagonist as a bolus of 0.31 mg/kg, followed by a 4-h infusio n of 0.5 mg/kg/h. rt-PA was administered as a modification of the weig ht adjusted standard regimen. Heparin was administered as a bolus foll owed by an infusion producing a 1.5- to 2-fold increase in the activat ed prothromboplastin time (aPTT) above baseline values. Aspirin was ad ministered orally, similar to 24 and 2 h before TP-9201. TP-9201 had a plasma clearance of 9.9 +/- 2 ml/min/kg and a volume of distribution that was larger than plasma volume. Administration of heparin and aspi rin with TP-9201 did not affect the clearance of TP-9201, whereas rt-P A resulted in a faster clearance (p = 0.05). Whether the faster cleara nce is physiologic or a result of rt-PA interference in the TP-9201 as say is unclear. TP-9201 completely inhibited ADP-mediated platelet agg regation. After discontinuation of TP-9201, recovery of platelet aggre gation had a half life (t(1/2)) of 2-3 h and was complete less than or equal to 24 h. Coadministration of heparin did not interfere with TP- 9201 pharmacodynamics, whereas aspirin and rt-PA slowed the recovery o f platelet aggregation. The template bleeding time profile for the TP- 9201-treated animals was similar to that of the aspirin-treated animal s.