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 recombinat tissue-type plasminogen activator (rt-PA) on TP-9201 pharmacokinetics and pharmacodynamics was investigated in beagles. Animals received TP-9201, an Arginine-Glycine-Aspartic acid (RGD)-containing synthetic peptide glycoprotein (gp)IIbIIIa antagonist as a bolus of 0.31 mg/kg, followed by a 4-h infusion of 0.5 mg/kg/h. rt-PA was administered as a modification of the weight-adjusted standard regimen. Heparin was administered as a bolus followed by an infusion producing a 1.5- to 2-fold increase in the activated prothromboplastin time (aPTT) above baseline values. Aspirin was administered orally, approximately 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 aspirin with TP-9201 did not affect the clearance of TP-9201, whereas rt-PA resulted in a faster clearance (p = 0.05). Whether the faster clearance is physiologic or a result of rt-PA interference in the TP-9201 assay is unclear. TP-9201 completely inhibited ADP-mediated platelet aggregation. After discontinuation of TP-9201, recovery of platelet aggregation had a half life (t1/2) of 2-3 h and was complete < or = 24 h. Coadministration of heparin did not interfere with TP-9201 pharmacodynamics, whereas aspirin and rt-PA slowed the recovery of platelet aggregation. The template bleeding time profile for the TP-9201-treated animals was similar to that of the aspirin-treated animals.
Modi
N B
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Department of Pharmacokinetics and Metabolism, S. San Francisco, California 94080, USA.
Reynolds
T
T
Baughman
S A
SA
Thomas
D A
DA
Paasch
B D
BD
Smith
S Y
SY
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D004285:Dogs; D004359:Drug Therapy, Combination; D006493:Heparin / Q000494:pharmacology; D008297:Male; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010960:Plasminogen Activators / Q000008:administration & dosage / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology*
D000925:Anticoagulants; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; C085362:TP 9201; D006493:Heparin; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D001241:Aspirin