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A translational platform PBPK model for antibody disposition in the brain

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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.

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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].

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Kapoor Hall, Buffalo, NY, 14214-8033, USA

    Hsueh-Yuan Chang, Shengjia Wu & Dhaval K. Shah

  2. Quantitative Clinical Pharmacology/PK-PD, Modeling & Simulation, Immunology/Inflammation, UCB Pharmaceuticals, Brussels, Belgium

    Guy Meno-Tetang

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  1. Hsueh-Yuan Chang
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Appendix

Appendix

A glossary of parameters used to build the platform brain PBPK model for mAbs

Parameter

Units

Definition

\({Q}_{p}^{i}\)

L/h

Plasma flow to the tissue “i”

\({Q}_{BC}^{i}\)

L/h

Blood cell flow to the tissue “i”

\({L}^{i}\)

L/h

Lymph flow from the tissue “i”

\({Q}_{CSF}^{brain},\) \({Q}_{ISF}^{brain}\)

L/h

CSF and brain interstitial fluid formation rate

\({V}^{p}\), \({V}^{BC}\), \({V}^{LN}\)

L

Volume of central plasma, central blood cell and lymph node compartments

\({V}_{BBB}^{brain}\), \({V}_{BCSFB}^{brain}\), \({V}_{LV}^{brain}\), \({V}_{TFV}^{brain}\), \({V}_{CM}^{brain}\), \({V}_{SAS(LS)}^{brain}\)

L

Volume of BBB endosomal, BCSFB endosomal, LV, TFV, CM and SAS compartments

\({V}_{p}^{i}\), \({V}_{BC}^{i}, {V}_{ES}^{i}\), \({V}_{IS}^{i}\)

L

Volume of vascular, blood cell, endosomal, and interstitial compartments for tissue “i”

\({C}^{p}\), \({C}^{BC}\), \({C}^{LN}\)

M

Concentration of mAb in central plasma, central blood cell and lymph node compartments

\({C}_{{BBB}_{unbound}}^{brain}\), \({C}_{{BBB}_{bound}}^{brain}\), \({C}_{{BCSFB}_{unbound}}^{brain}\), \({{C}_{{BCSFB}_{bound}}^{brain}}\), \({C}_{LV}^{brain}\), \({{C}_{TFV}^{brain}}\), \({C}_{CM}^{brain}\), \({C}_{SAS(LS)}^{brain}\)

M

Concentration of mAb in BBB endosomal (Unbound and Bound), BCSFB endosomal (Unbound and Bound), LV, TFV, CM and SAS compartments

\({C}_{p}^{i}\), \({C}_{BC}^{i}\), \({C}_{E\_unbound}^{i}\), \({C}_{E\_bound}^{i}\), \({C}_{IS}^{i}\)

M

Concentration of mAb in vascular, blood cell, endosomal (Unbound and Bound), interstitial and cellular (Bound) compartments for tissue “i”

\({FcRn}_{free}^{i}\)

M

Concentration of free FcRn in endosomal space

\({\sigma }_{V}^{i}\), \({\sigma }_{L}^{i}\)

–

Vascular and lymph reflection coefficient

\({\sigma }_{V}^{BBB}\), \({{\sigma }_{V}^{BCSFB}}\)

–

BBB and BCSFB vascular reflection coefficient

\({k}_{on}\)

1/M/h

Association rate constant between mAb-FcRn

\({k}_{off}\)

1/h

Dissociation rate constant between mAb-FcRn

FR

–

Fraction of FcRn bound mAb that recycles to the vascular space

\({f}_{BBB},\) \({f}_{BCSFB}\)

–

Surface area fractions of BBB and BCSFB

\({f}_{LV}\), \({f}_{TFV}\)

–

Volume fractions of LV and TFV

\(S{A}_{BBB}\), \(S{A}_{BCSFB}\)

L

Surface area of BBB and BCSFB

\(C{L}_{up}\), \({C{L}_{up}^{brain}}\)

L/h/L

Rate of pinocytosis and exocytosis per unit endosomal space for tissue and brain

\({k}_{deg}\)

1/h

First order degradation rate constant of FcRn unbound mAb within the endosomal space

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Chang, HY., Wu, S., Meno-Tetang, G. et al. A translational platform PBPK model for antibody disposition in the brain. J Pharmacokinet Pharmacodyn 46, 319–338 (2019). https://doi.org/10.1007/s10928-019-09641-8

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  • DOI: https://doi.org/10.1007/s10928-019-09641-8

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