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Vol. 298, Issue 1, 165-171, July 2001

Pharmacokinetics, Pharmacodynamics, and Platelet Binding of an Anti-Glycoprotein IIb/IIIa Monoclonal Antibody (7E3) in the Rat: A Quantitative Rat Model of Immune Thrombocytopenic Purpura

Ryan J. Hansen and Joseph P. Balthasar

Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York

The pharmacokinetics, pharmacodynamics, and platelet binding of 7E3, an anti-glycoprotein IIb/IIIa (GPIIb/IIIa) monoclonal antibody, were studied in the rat in an attempt to develop a quantitative animal model of immune thrombocytopenia (ITP). 7E3, a murine IgG1 antibody developed against human GPIIb/IIIa, demonstrated cross-reactivity with rat platelets by flow cytometry and via enzyme-linked immunosorbent assay. The apparent affinity (KA) of 7E3-rat platelet binding was 1.2 ± 0.2 × 107 M-1, with 3.3 ± 0.3 × 104 binding sites per platelet. Following intravenous 7E3 administration (0.8, 4, and 8 mg/kg), plasma concentrations declined in a bi-exponential manner, with a terminal half-life of 61 ± 5 h and a steady-state volume of distribution of 62 ± 15 ml/kg. Clearance was dose-dependent, with values ranging from 0.64 ± 0.08 ml/h/kg (8 mg/kg) to 1.01 ± 0.08 ml/h/kg (0.8 mg/kg). 7E3 induced a reproducible, severe thrombocytopenia in rats and extended bleeding in a manner consistent with human ITP. Nadir platelet counts were 79 ± 33, 25 ± 6, and 17 ± 2 × 106/ml, for 7E3 doses of 0.8, 4, and 8 mg/kg, respectively. Bleeding times after a 10-mm tail incision ranged from 5 ± 3 min in control animals to 15 ± 0 min (the maximum allowed time in this study) in animals receiving 8 mg/kg. Blood volumes lost during bleeding experiments ranged from 30 ± 24 µl (control) to 349 ± 358 µl (8 mg/kg). A reproducible, quantitative rat model of ITP has been created; this model is expected to facilitate the evaluation of new treatments for this disease.

0022-3565/01/2981-0165$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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