Evaluation of a catenary PBPK model for predicting the in vivo disposition of mAbs engineered for high-affinity binding to FcRn.

ABSTRACT: Efforts have been made to extend the biological half-life of monoclonal antibody drugs (mAbs) by increasing the affinity of mAb-neonatal Fc receptor (FcRn) binding; however, mixed results have been reported. One possible reason for a poor correlation between the equilibrium affinity of mAb-FcRn binding and mAb systemic pharmacokinetics is that the timecourse of endosomal transit is too brief to allow binding to reach equilibrium. In the present work, a new physiologically based pharmacokinetic (PBPK) model has been developed to approximate the pH and time-dependent endosomal trafficking of immunoglobulin G (IgG). In this model, a catenary sub-model was utilized to describe the endosomal transit of IgG and the time dependencies in IgG-FcRn association and dissociation. The model performs as well as a previously published PBPK model, with assumed equilibrium kinetics of mAb-FcRn binding, in capturing the disposition profile of murine mAb from wild-type and FcRn knockout mice (catenary vs. equilibrium model: r (2), 0.971 vs. 0.978; median prediction error, 3.38% vs. 3.79%). Compared to the PBPK model with equilibrium binding, the present catenary PBPK model predicts much more moderate changes in half-life with altered FcRn binding. For example, for a 10-fold increase in binding affinity, the catenary model predicts <2.5-fold change in half-life compared to an ?8-fold increase as predicted by the equilibrium model; for a 100-fold increase in binding affinity, the catenary model predicts ?7-fold change in half-life compared to >70-fold increase as predicted by the equilibrium model. Predictions of the new catenary PBPK model are more consistent with experimental results in the published literature.

SUBMITTER: Chen Y 

PROVIDER: S-EPMC3475865 | biostudies-other | 2012 Dec

REPOSITORIES: biostudies-other