Pharmacokinetic and pharmacodynamic effects of 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 or 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 approximately 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.
Jin
Feng
F
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.
Tayab
Zia R
ZR
Balthasar
Joseph P
JP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D051381:Rats; D017207:Rats, Sprague-Dawley; D013921:Thrombocytopenia / Q000276:immunology* / Q000628:therapy*
D000911:Antibodies, Monoclonal