Two-Pore Minimum Physiologically-based Pharmacokinetic Model to Describe the Disposition of Therapeutic Monoclonal IgG Antibody in Humans

Deni Hardiansyah, Chee Meng Ng

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Purpose: The aim of this study was to develop a two-pore minimum physiologically-based pharmacokinetic (mPBPK) model in describing the pharmacokinetic (PK) of therapeutic monoclonal antibody (TMAb) in human subjects. Methods: PK data used in this study were endogenous/exogenous native IgG and two TMAbs (palivizumab and Motavizumab-YTE) in normal volunteer or familial hypercatabolic hypoproteinemia (FIHH) patient. Several important components were implemented to overcome the limitations of the early mPBPK model, e.g. two-pore model to describe the transcapillary transport of IgG from vascular to interstitial space. Six mPBPK models with different osmotic reflection coefficient (OFC) of transcapillary transport, endocytosis rates (ETR) and plasma clearance for the TMAbs/IgG were tested and the best model was selected using AICc values. Results: The final model consisted of different OFC and ETR values for native IgG and TMAbs, supporting the hypothesis that the dynamics in the endosomal space had an important role in the compliant FcRn salvage mechanism to determine the clearance of TMAbs. The estimated FcRn concentration of FIHH subjects was 2.72 μmol/l. The final two-pore mPBPK model has a better performance for native IgG than previously developed mPBPK model. Conclusions: The final two-pore mPBPK model not only overcome the limitations of the early mPBPK model but also has a better performance to describe the disposition of the IgG antibody in human subjects.

Original languageEnglish
Article number47
JournalPharmaceutical Research
Volume35
Issue number3
DOIs
Publication statusPublished - 1 Mar 2018

Keywords

  • IgG
  • motavizumab-YTE
  • mPBPK model
  • palivizumab
  • two-pore model

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