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Computer-assembled cross-species/cross-modalities two-pore physiologically based pharmacokinetic model for biologics in mice and rats

  • Armin SeppEmail author
  • Guy Meno-Tetang
  • Andrew Weber
  • Andrew Sanderson
  • Oliver Schon
  • Alienor Berges
Original Paper
  • 356 Downloads

Abstract

Two-pore physiologically-based pharmacokinetic (PBPK) models can be expected to describe the tissue distribution and elimination kinetics of soluble proteins, endogenous or dosed, as function of their size. In this work, we amalgamated our previous two-pore PBPK model for an inert domain antibody (dAb) in mice with the cross-species platform PBPK model for monoclonal antibodies described in literature into a unified two-pore platform that describes protein modalities of different sizes and includes neonatal Fc receptor (FcRn) mediated recycling. This unified PBPK model was parametrized for organ-specific lymph flow rates and the endosomal recycling rate constant using an extended tissue distribution time-course dataset that included an inert dAb, albumin and IgG in rats and mice. The model was evaluated by comparing the ab initio predictions for the tissue distribution and elimination properties of albumin-binding dAbs (AlbudAbsTM) in mice and rats with the experimental observations. Due to the large number of molecular species and reactions involved in large-scale PBPK models, we have also developed and deployed a MatlabTM script for automating the assembly of SimBiologyTM-based two-pore biologics PBPK models which drastically cuts the time and effort required for model building.

Keywords

Domain antibody AlbudAbTM Albumin Antibody Physiologically based pharmacokinetics 

Notes

Acknowledgements

Milan Ovecka, Ed Coulstock, Leigh-Ann Booth, Laurent Jespers, Valeriu Damian-Iordache, Indranil Rao and Gaohua Lu, for generously sharing the data, supporting the study and revising the manuscript.

Supplementary material

10928_2019_9640_MOESM1_ESM.docx (6 mb)
Supplementary material 1 (DOCX 5626 kb)

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Authors and Affiliations

  1. 1.Systems Modeling and Translational Biology, 1F307 Glaxo Medicines Research CentreGlaxoSmithKlineStevenageUK
  2. 2.Systems Modeling and Translational BiologyGlaxoSmithKlineKing of PrussiaUSA
  3. 3.PCS R&D, GlaxoSmithKlineStevenageUK
  4. 4.AgenusBioCambridgeUK
  5. 5.Clinical Pharmacology, Modelling and SimulationGlaxoSmithKlineUxbridgeUK
  6. 6.Modeling & Simulation, Immunology/Inflammation, UCB PharmaceuticalsSloughUK
  7. 7.Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech UnitAstraZenecaCambridgeUK

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