Pharmacokinetic/pharmacodynamic modeling of IVIG effects in a murine model of immune thrombocytopenia.
IVIG may achieve its beneficial effects in immune thrombocytopenia (ITP) patients via several mechanisms; however, little is known of the relative importance of various mechanisms associated with IVIG action in ITP. The purposes of this study were to develop a pharmacokinetic/pharmacodynamic (PK/PD) model relating an anti-platelet antibody, MWReg30, to platelet counts in a mouse model of sustained ITP, to use modeling to characterize effects of IVIG on MWReg30 elimination, and to use PK/PD modeling to assess the contribution of IVIG effects on MWReg30 disposition to the effects of IVIG on MWReg30-induced thrombocytopenia in mice. A pharmacokinetic model, based on the competitive occupancy of protective FcRn receptors, was used to characterize the effects of IVIG on MWReg30 pharmacokinetics. The relationships between MWReg30 plasma concentrations to MWReg30-induced thrombocytopenia, in the presence and absence of IVIG treatment, were characterized using an indirect response model. The pharmacokinetic model well-captured MWReg30 plasma concentration-time profiles, with and without administration of IVIG. The indirect response model accurately characterized the effects of IVIG on MWReg30-induced thrombocytopenia in mice. Using these models, it was estimated that 43 +/- 5% of overall effects of IVIG on MWReg30-induced thrombocytopenia in mice could be accounted for by the IVIG-mediated increases in MWReg30 clearance.
Deng
Rong
R
Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
Balthasar
Joseph P
JP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D001792:Blood Platelets / Q000276:immunology*; D004195:Disease Models, Animal; D007074:Immunoglobulin G / Q000378:metabolism; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D008657:Metabolic Clearance Rate; D051379:Mice; D008954:Models, Biological; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D013926:Thrombopoietin / Q000097:blood
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D013926:Thrombopoietin