Pharmacokinetic/pharmacodynamic modeling of the effects of intravenous immunoglobulin on the disposition of antiplatelet antibodies in a rat model of immune thrombocytopenia.
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 lacking expression of the FcRn receptor. An indirect response PK/PD model was also developed, which accurately characterized 7E3 effects on platelet counts. Using these models, it was estimated that 50 +/- 11% of the total protective effect of IVIG in this acute model of ITP can be accounted for by IVIG effects on 7E3 disposition.
Hansen
Ryan J
RJ
Department of Pharmaceutical Sciences, University at Buffalo, The State University at New York, Buffalo, New York 14260, USA.
Balthasar
Joseph P
JP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology; D001792:Blood Platelets / Q000276:immunology*; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G / Q000276:immunology; D016756:Immunoglobulins, Intravenous / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011961:Receptors, Fc / Q000378:metabolism; D013997:Time Factors
D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D011961:Receptors, Fc; C100688:Fc receptor, neonatal