Reproducibility Study on a PBPK Model of FcRn-Mediated Recycling for Large Molecules

Abstract

The PBPK model of FcRn-mediated recycling of large molecules was developed and studied by \cite{de2023mechanistic} to characterize and predict Immunoglobulin G (IgG) disposition in plasma and tissues. This study investigated the large-molecule model in PK-Sim and its applicability to molecules with FcRn binding affinity in plasma. Subsequently, the model was extended to ensure a more mechanistic description of the internalization of FcRn and the FcRn-drug complex. This PBPK model has applications in autoimmune disorders such as primary immune thrombocytopenia which is mediated partly by platelet autoantibodies, resulting in thrombocytopenia, bleeding, and constitutional symptoms. Currently, there are several FcRn inhibitors in clinical development for numerous indications that can benefit from this model. We created a modular implementation of the model in MoBi, which is able to reproduce the originally published data. This Physiome paper describes how to access, run, and manipulate this model, how to parameterize the model to match data, and how to compare model predictions to data. In addition, some inconsistencies have been revealed and discussed in this paper. EDITOR'S NOTE v2: adding OMEX archive. v3: correcting file names. v4: updating publication date. v5: updating OMEX archive. v6: attaching CRBM report.