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A translational platform PBPK model for antibody disposition in the brain

  • Hsueh-Yuan Chang
  • Shengjia Wu
  • Guy Meno-Tetang
  • Dhaval K. ShahEmail author
Original Paper

Abstract

In this manuscript, we have presented the development of a novel platform physiologically-based pharmacokinetic (PBPK) model to characterize brain disposition of mAbs in the mouse, rat, monkey and human. The model accounts for known anatomy and physiology of the brain, including the presence of distinct blood–brain barrier and blood–cerebrospinal fluid (CSF) barrier. CSF and interstitial fluid turnover, and FcRn mediated transport of mAbs are accounted for. The model was first used to characterize published and in-house pharmacokinetic (PK) data on the disposition of mAbs in rat brain, including the data on PK of mAb in different regions of brain determined using microdialysis. Majority of model parameters were fixed based on literature reported values, and only 3 parameters were estimated using rat data. The rat PBPK model was translated to mouse, monkey, and human, simply by changing the values of physiological parameters corresponding to each species. The translated PBPK models were validated by a priori predicting brain PK of mAbs in all three species, and comparing predicted exposures with observed data. The platform PBPK model was able to a priori predict all the validation PK profiles reasonably well (within threefold), without estimating any parameters. As such, the platform PBPK model presented here provides an unprecedented quantitative tool for prediction of mAb PK at the site-of-action in the brain, and preclinical-to-clinical translation of mAbs being developed against central nervous system (CNS) disorders. The proposed model can be further expanded to account for target engagement, disease pathophysiology, and novel mechanisms, to support discovery and development of novel CNS targeting mAbs.

Keywords

Brain Monoclonal antibody Pharmacokinetics PBPK model Interspecies scaling Blood–brain barrier Blood–CSF barrier 

Notes

Acknowledgements

This work was supported by the Centre for Protein Therapeutics at University at Buffalo. D.K.S is supported by National Institute of Health Grant [GM114179] and [AI138195].

Supplementary material

10928_2019_9641_MOESM1_ESM.docx (40 kb)
Supplementary file1 (DOCX 39 kb)

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Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical SciencesThe State University of New York at BuffaloBuffaloUSA
  2. 2.Quantitative Clinical Pharmacology/PK-PD, Modeling & Simulation, Immunology/InflammationUCB PharmaceuticalsBrusselsBelgium

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