Disposition and exposure of the fibrinogen receptor antagonist XV459 on αIIBβ3 binding sites in the guinea pig

Abstract

The disposition of XV459, a potent, selective GP IIb/IIIa antagonist, has been examined following intravenous administration of XP280, the benzenesulphonate salt, and 3H‐SA202, the trifluroacetic acid salt, to male guinea pigs. 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 μg/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. Maximum total (unbound and GP IIb/IIIa displaced) XV459 plasma concentration of approximately 3.5 ng/mL was obtained at the 2.0 μg/kg dose. Pooling individual concentration–time data yielded a systemic clearance of 1.42 mL/min/kg, Vss of 0.24 L/kg, and a terminal half‐life of 2.8 h in the guinea pig at the 0.5 μg/kg dose. The 2.0 μg/kg dose yielded XV459 exposure that was less than proportional to the previous dose. Similar behaviour has been observed in human trials. Cumulative (up to 72 h) urinary and faecal recovery of total radioactivity was 66.4 and 11.2%, respectively. The time course of spleen, marrow and whole blood radioactivity profiles was similar, suggesting that XV459 was not preferentially sequestered on non‐plasma GP IIb/IIIa 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) exposure was evident for sites containing the GP IIb/IIIa receptor. In vitro studies confirmed the similarity of XV459 binding to both resting and activated platelets in the guinea pig and humans. Given the comparability of dissociation rate constants and IC50s based on in vitro platelet aggregation, human dosimetry estimates should assume similar partitioning of radiolabelled XV459 as in the guinea pig. These results suggest that the guinea pig may indeed be an appropriate animal model for pharmacokinetic and distribution 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 © 1999 John Wiley & Sons, Ltd.

Pharmacokinetic/Pharmacodynamic Studies in Drug Product Development

“…Narjes et al18 evaluated the use of inhibition of ex vivo platelet aggregation as surrogate for PD activity of glycoprotein IIb/IIIa receptor antagonists. Barrett et al 19 identified the guinea pig as the most appropriate rodent species to investigate the PK/PD of glycoprotein IIb/IIIa inhibitors due to PD similarities with humans in drug/receptor binding.…”

A Rational Approach to Drug Development: The Exploratory Phase

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Safety, Tolerability, Pharmacokinetics, and Time Course of Pharmacologic Response of the Active Metabolite of Roxifiban, XV459, a Glycoprotein IIb/IIIa Antagonist, following Oral Administration in Healthy Volunteers

“…It provides prolonged antiplatelet effects in dogs and guinea pigs. [19][20][21] The objective of this study was to determine the safety, tolerability, pharmacokinetics, and time course of pharmacologic response following administration of single and multiple escalating oral doses of roxifiban to healthy young (ages 18-46 years) and older (ages 47-75 years) adult populations. We also studied these parameters in subjects exposed to aspirin prior to roxifiban administration versus subjects naive to antiplatelet therapy.…”