Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jun;49(3):337-362.
doi: 10.1007/s10928-021-09800-w. Epub 2022 Jan 29.

Towards a translational physiologically-based pharmacokinetic (PBPK) model for receptor-mediated transcytosis of anti-transferrin receptor monoclonal antibodies in the central nervous system

Hsueh-Yuan Chang  1   2 , Shengjia Wu  1 , Ekram Ahmed Chowdhury  1 , Dhaval K Shah  3
Affiliations

Towards a translational physiologically-based pharmacokinetic (PBPK) model for receptor-mediated transcytosis of anti-transferrin receptor monoclonal antibodies in the central nervous system

Hsueh-Yuan Chang et al. J Pharmacokinet Pharmacodyn. 2022 Jun.

Abstract

In this manuscript, we present a translational physiologically-based pharmacokinetic (PBPK) model to characterize receptor-mediated transcytosis (RMT) of anti-transferrin receptor (TfR) monoclonal antibodies (mAbs) in the central nervous system (CNS). The model accounts for the state-of-the-art knowledge of the brain's anatomy and physiology, and physiological parameters were fixed according to different species. By estimating a few parameters associated with the TfR concentration, the TfR turnover, and the internalization rate, the model simultaneously characterizes plasma, whole brain, interstitial fluid (ISF), and cerebrospinal fluid (CSF) PK of unbound and bound anti-TfR mAbs with different binding affinities in mice, rats, and monkeys obtained from various literature sources within a threefold prediction error. The final PBPK model was validated using external anti-TfR mAb PK data in mice and monkeys with different affinities and doses. The simulation reasonably predicted plasma and brain PK of monovalent/bivalent anti-TfR mAbs within a threefold prediction error and characterized a bell-shaped relationship between the brain ISF/plasma AUC ratio and the KD value. Although further refinements of the PBPK model and clinical validation are required, this PBPK model may provide physiologically-based translation of CNS disposition of anti-TfR mAbs by accounting for the physiological difference of the endogenous RMT system among different species. The PBPK model may also guide selection of other endogenous receptors, lead optimization, and clinical development of novel CNS-targeted mAbs.

Keywords: Brain; Monoclonal antibody; PBPK model; Pharmacokinetics; Receptor-mediated transcytosis; TfR.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

References

    1. Vendel E, Rottschafer V, de Lange ECM (2019) The need for mathematical modelling of spatial drug distribution within the brain. Fluids Barriers CNS 16(1):12 - PubMed - PMC - DOI
    1. Pardridge WM (2019) Alzheimer’s disease: future drug development and the blood-brain barrier. Expert Opin Investig Drugs 28(7):569–572 - PubMed - DOI
    1. Wang Q, Delva L, Weinreb PH, Pepinsky RB, Graham D, Veizaj E, Cheung AE, Chen W, Nestorov I, Rohde E, Caputo R, Kuesters GM, Bohnert T, Gan LS (2018) Monoclonal antibody exposure in rat and cynomolgus monkey cerebrospinal fluid following systemic administration. Fluids Barriers CNS 15(1):10 - PubMed - PMC - DOI
    1. Yadav DB, Maloney JA, Wildsmith KR, Fuji RN, Meilandt WJ, Solanoy H, Lu Y, Peng K, Wilson B, Chan P, Gadkar K, Kosky A, Goo M, Daugherty A, Couch JA, Keene T, Hayes K, Nikolas LJ, Lane D, Switzer R, Adams E, Watts RJ, Scearce-Levie K, Prabhu S, Shafer L, Thakker DR, Hildebrand K, Atwal JK (2017) Widespread brain distribution and activity following icv infusion of anti-beta-secretase (BACE1) in nonhuman primates. Br J Pharmacol 174(22):4173–4185 - PubMed - PMC - DOI
    1. Pizzo ME, Wolak DJ, Kumar NN, Brunette E, Brunnquell CL, Hannocks MJ, Abbott NJ, Meyerand ME, Sorokin L, Stanimirovic DB, Thorne RG (2018) Intrathecal antibody distribution in the rat brain: surface diffusion, perivascular transport and osmotic enhancement of delivery. J Physiol 596(3):445–475 - PubMed - DOI

Publication types

Substances

LinkOut - more resources