Pharmacokinetic/pharmacodynamic modeling of the effects of intravenous immunoglobulin on the disposition of antiplatelet antibodies in a rat model of immune thrombocytopenia

Journal of Pharmaceutical Sciences
Ryan J Hansen, Joseph P Balthasar

Abstract

Recently, our laboratory reported that intravenous immunoglobulin (IVIG) treatment increased antiplatelet antibody (7E3) clearance in a rat model of immune thrombocytopenic purpura (ITP). However, due to the multifaceted nature of IVIG therapy, the contribution of this increase in antiplatelet antibody clearance to the total therapeutic effect of IVIG was unclear. The purposes of the present study were to (1). develop a new, mechanistic model of immune gamma globulin (IgG) pharmacokinetics, (2). develop a pharmacokinetic/pharmacodynamic (PK/PD) model relating 7E3 concentrations to the platelet count time course observed following 7E3 treatment, and (3). use these mathematical models to gain insight into the significance of increased 7E3 clearance relative to the total effect of IVIG on 7E3-induced thrombocytopenia. A mechanism-based PK model was developed that adequately characterized IVIG effects on 7E3 pharmacokinetics. The structure of this model is based on competition between IgG molecules for occupancy of the protective FcRn receptor. The model accurately captured antiplatelet antibody concentration versus time data in the presence and absence of IVIG therapy, in the rat, in 'wild-type' mice, and in 'knockout' mice lackin...Continue Reading

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