Pharmacokinetics and pharmacodynamics of TP-9201, a GPIIbIIIa antagonist, in rats and dogs.

Because activation of the glycoprotein IIbIIIa (GPIIbIIIa) on platelets represents the final common pathway of platelet aggregation, inhibition of fibrinogen binding to the GPIIbIIIa complex provides an excellent target for inhibiting platelet aggregation. Peptides containing the arginine-glycine-aspartic acid (RGD) sequence have been shown to inhibit the binding of fibrinogen to the GPIIbIIIa receptor on platelets competitively. We studied the pharmacokinetics of TP-9201, a synthetic cyclic peptide containing the RGD sequence, in rats and dogs after a 24-h intravenous (I.V.) infusion at three doses. The mean plasma clearance of TP-9201 after intravenous infusions of 30, 150, and 600 mg/kg/day in rats was 20.2, 18.7, and 18.5 ml/min/kg, respectively. In beagles, TP-9201 clearance was 9.0, 7.5, and 7.3 ml/min/kg, corresponding to infusions of 10, 75, and 600 mg/kg/day, respectively. The volume of distribution was larger than plasma volume, and the terminal half-life (t1/2) was short in both species studied ranging from 0.5 to 0.7 h in rats and from 2.5 to 2.6 h in dogs. The results suggest that TP-9201 follows linear pharmacokinetics over the dose range studied. Despite the multiple blood sampling procedure used in the study, there were no hemorrhagic complications. Pharmacodynamic assessment in beagles showed that TP-9201 produces a dose-dependent inhibition of ADP-mediated platelet aggregation. The estimated in vivo IC50 value and sigmoidicity were 124 and 3.5 ng/ml, respectively, suggesting that TP-9201 is a potent GPIIbIIIa antagonist with a steep concentration-effect relationship. TP-9201 is rapidly cleared from the circulation on termination of the intravenous infusion. There is a corresponding reversal of platelet inhibition as TP-9201 is cleared from the circulation.