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

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Abstract

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 ≈8% of initial values within 1 hour after 7E3 administration. AMI pretreatment dramatically affected 7E3-induced thrombocytopenia, significantly altering the time course of throm-bocytopenia (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.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 14260, Buffalo, NY

    Feng Jin, Zia R. Tayab & Joseph P. Balthasar

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  1. Feng Jin
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  2. Zia R. Tayab
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  3. Joseph P. Balthasar
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Correspondence to Joseph P. Balthasar.

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Published: January 13, 2006

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Jin, F., Tayab, Z.R. & Balthasar, J.P. Pharmacokinetic and pharmacodynamic effects of high-dose monoclonal antibody therapy in a rat model of immune thrombocytopenia. AAPS J 7, 87 (2005). https://doi.org/10.1208/aapsj070487

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  • DOI: https://doi.org/10.1208/aapsj070487

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