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.

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 (K(A)) of 7E3-rat platelet binding was 1.2 +/- 0.2 x 10(7) M(-1), with 3.3 +/- 0.3 x 10(4) 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 x 10(6)/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 microl (control) to 349 +/- 358 microl (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.