Evaluation of a Catenary PBPK Model for Predicting the In Vivo Disposition of mAbs Engineered for High-Affinity Binding to FcRn

• Published in: The AAPS journal Vol. 14; no. 4; pp. 850 - 859
• Main Authors: Chen, Yang, Balthasar, Joseph P.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-12-2012
• Subjects: Animals; Antibodies, Monoclonal - pharmacokinetics; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Endosomes - metabolism; Half-Life; Hydrogen-Ion Concentration; Immunoglobulin G - metabolism; Mice; Mice, Knockout; Models, Biological; Pharmacology/Toxicology; Pharmacy; Protein Binding; Receptors, Fc - genetics; Receptors, Fc - metabolism; Research Article; Time Factors; FcRn; PBPK; pharmacokinetics; endosomal transit; mAb
• ISSN: 1550-7416; 1550-7416
• DOI: 10.1208/s12248-012-9395-9

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.