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. 2021 Aug 10;48(6):861–871. doi: 10.1007/s10928-021-09776-7

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© The Author(s) 2021

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — Brain mPBPK model structure. The model contains 16 compartments and three regions: plasma (red), brain (blue) and non-brain tissues (green). Antibodies in plasma flow between brain and non-brain tissues. In tissue vascular, antibody travels transcellularly through the endosomal space or paracellularly by directly entering tissue interstitium. In the endosome, antibody binds FcRn to form an antibody-FcRn complex, which either is taken up into the tissue interstitial space or recycled back to the tissue vasculature. Unbound antibody in the endosome is cleared through lysosomal degradation. Antibody in tissue interstitial space leaves via lymphatic flow as well as via endosomal uptake. Antibody in brain vasculature crosses two brain barriers, BBB and BCSFB. Antibodies that cross the BBB and BCSFB enter the brain ISF and CSF, respectively. Paracellular transport across the BBB and BCSFB is governed by brain vascular reflection coefficients that represent the leakiness of the vasculature space. Transcellular transport across the brain via pinocytosis is described by uptake clearance processes. Antibody in brain endosomal spaces is either recycled via FcRn or eliminated via lysosomal degradation. Antibody in brain ISF and CSF can be cleared back to systemic circulation via the glymphatic system. Diagram was drawn using Inkscape (Color figure online)