The AAPS Journal

, 20:48 | Cite as

A Minimal Physiologically Based Pharmacokinetic Model with a Nested Endosome Compartment for Novel Engineered Antibodies

Research Article


We proposed here a minimal physiologically based pharmacokinetic (mPBPK) model for a group of novel engineered antibodies in mice and humans. These antibodies are designed with altered binding properties of their Fc domain with neonatal Fc receptor (FcRn) or the Fab domain with their cognate targets (recycling antibodies) in acidic endosomes. To enable simulations of such binding features in the change of antibody pharmacokinetics and its target suppression, we nested an endothelial endosome compartment in parallel with plasma compartment based on our previously established mPBPK model. The fluid-phase pinocytosis rate from plasma to endothelial endosomes was reflected by the clearance of antibodies in FcRn dysfunctional humans or FcRn-knockout mice. The endosomal recycling rate of FcRn-bound antibodies was calculated based on the reported endosomal transit time. The nonspecific catabolism in endosomes was fitted using pharmacokinetic data of a human wild-type IgG1 adalimumab in humans and B21M in human FcRn (hFcRn) transgenic mice. The developed model adequately predicted the pharmacokinetics of infliximab, motavizumab, and an Fc variant of motavizumab in humans and the pharmacokinetics of bevacizumab, an Fc variant of bevacizumab, and a recycling antibody PH-IgG1 and its non-pH dependent counterpart NPH-IgG1 in hFcRn transgenic mice. Our proposed model provides a platform for evaluation of the pharmacokinetics and disposition behaviors of Fc-engineered antibodies and recycling antibodies.


endosome FcRn mPBPK model pharmacokinetics recycling antibody 



This work was supported by grants from NIH (R35 GM119661).

Compliance with Ethical Standards

Conflict of Interest

F. Rode is an employee of Novo Nordisk, Denmark.

Supplementary material

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Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.Novo NordiskMåløvDenmark
  3. 3.Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillChapel HillUSA

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