Pharmacokinetic/pharmacodynamic modeling of IVIG effects in a murine model of immune thrombocytopenia.

Abstract

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.