Pharmacokinetic and pharmacodynamic effects on high-dose monoclonal antibody therapy in a rat model of immune thrombocytopenia

Intravenous administration of pooled, polyvalent human immunoglobulin (IVIG) has been used for over 20 years as a therapy for immune thrombocytopenia (ITP). IVIG is available in limited quantities, and clinical preparations have been associated with the transfer of human pathogens. We have proposed that high-dose monoclonal antibody may be used in lieu of IVIG to achieve beneficial effects in the treatment of ITP. The current study investigates the effects of high-dose monoclonal antibody therapy in a rat model of ITP. Hybridoma cells secreting a murine monoclonal antiplatelet antibody (7E3) and murine monoclonal anti-methotrexate IgG (AMI) were grown in serum-free media. Next, 7E3, 8 mg kg^-1 was administered intravenously to rats following pretreatment with saline AMI (1 g kg^-1 IV). AMI and 7E3 plasma concentrations were determined via enzyme-linked immunosorbent assay, and platelet count was determined with a Cell-Dyne hematology analyzer. Severe, transient thrombocytopenia was induced by 7E3. Platelet counts dropped to ∼8% of initial values within 1 hour after 7E3 administration. AMI pretreatment dramatically affected 7E3-induced thrombocytopenia, significantly altering the time course of thrombocytopenia (P < .05) and significantly decreasing the severity of 7E3-induced thrombocytopenia (ie, following AMI pretreatment, nadir platelet count was greater than 8-fold that of the control group, P < .05). In addition, AMI pretreatment induced a 57% increase in 7E3 clearance (1.13 ± 0.13 mL h^-1 kg^-1 vs 0.72 ± 0.08 mL h^-1 kg^-1, P < .05). Consequently, high-dose monoclonal antibody therapy attenuated thrombocytopenia and produced a moderate increase in the clearance of antiplatelet antibodies in a rat model of ITP.