Minimal physiologically-based pharmacokinetic model to investigate the effect of pH dependent FcRn affinity and the endothelial endocytosis on the pharmacokinetics of anti-VEGF humanized IgG1 antibody in cynomolgus monkey

摘要

In this study, we developed a first minimal physiologically-based pharmacokinetic (mPBPK) model to investigate the complex interaction effects of endocytosis rate/FcRn binding affinity at both acidic/physiological pH on the pharmacokinetics (PK) of the anti-VEGF IgG(1) antibodies. The data used in this study were the PK of the native IgG and humanized anti-VEGF IgG(1) antibodies with a wide range FcRn-binding at both acidic and physiological pH in the cynomolgus monkey. The basic structure of the developed mPBPK models consisted of plasma, tissue and lymph compartments. The tissue compartment was subdivided into vascular, endothelial and interstitial spaces. Non-equilibrium binding mechanism was used to describe the FcRn-IgG interaction in the endosome. The fittings in the final model with three pH systems in the endosome compartment showed a good fit based on the visualization of the fitted graphs and the coefficient of variations of the estimated parameters (CV 50%). The quantitative endocytosis/FcRn binding affinity PK relationships was constructed using the final model to provide better understanding of complex interaction effects of endocytosis rate and FcRn binding on PK of anti-VEGF IgG(1) antibodies. This result may serve as an important model-based drug discovery platform to guide the design and development of the future generation of anti-VEGF IgG(1) or other therapeutic IgG(1) antibodies. In addition, the mPBPK model developed in cynomolgus monkey was successfully used to predict the PK of the anti-VEGF IgG(1) antibody (bevacizumab) in human subjects.