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Abstract

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 (<i>K</i>_A) 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.

Keywords

Affiliated Institutions

• British Heart Foundation GB
• Glenfield Hospital GB

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