Disposition and exposure of the fibrinogen receptor antagonist XV459 on alpha(IIB)beta(3), binding sites in the guinea pig

The disposition of XV459, a potent, selective GP IIb/IIIa antagonist, has b een examined following intravenous administration of XP280, the benzenesulp honate salt, and H-3-SA202, the trifluroacetic acid salt, to male guinea pi gs. A Liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for XV459 quantitation in guinea pig plasma with an LLOQ of 0 .1 ng/mL. Intravenous infusions (30 min) of XP280 at doses of 0.5 and 2.0 m u g/kg were administered to guinea pigs which were sequentially sacrificed at 0.5, 1, 1.5, 4, 8, 12, 24, 48 and 72 h postinitiation of infusion. Maxim um total (unbound and GP IIb/IIIa displaced) XV459 plasma concentration of approximately 3.5 ng/mL was obtained at the 2.0 mu g/kg dose. Pooling indiv idual concentration-time data yielded a systemic clearance of 1.42 mL/min/k g, V-ss of 0.24 L/kg, and a terminal half-life of 2.8 h in the guinea pig a t the 0.5 mu g/kg dose. The 2.0 mu g/kg dose yielded XV459 exposure that wa s less than proportional to the previous dose. Similar behaviour has been o bserved in human trials. Cumulative (up to 72 h) urinary and faecal recover y of total radioactivity was 66.4 and 11.2%, respectively. The time course of spleen, marrow and whole blood radioactivity profiles was similar, sugge sting that XV459 was not preferentially sequestered on non-plasma GP IIb/II Ia binding sites. Tissue to blood ratios of 20.7 and 8.3 for the spleen and bone marrow, respectively, indicate that increased (relative to blood) exp osure was evident for sites containing the GP IIb/IIIa receptor. In vitro s tudies confirmed the similarity of XV459 binding to both resting and activa ted platelets in the guinea pig and humans. Given the comparability of diss ociation rate constants and IC(50)s based on in vitro platelet aggregation, human dosimetry estimates should assume similar partitioning of radiolabel led XV459 as in the guinea pig. These results suggest that the guinea pig m ay indeed be an appropriate animal model for pharmacokinetic and distributi on studies with DMP754; in conjunction with recent pharmacological findings with GP IIb/IIIa antagonists, our results suggest that the guinea pig may be the rodent species of choice for preclinical studies with some other GP IIb/IIIa antagonists. Copyright (C) 1999 John Wiley & Sons, Ltd.