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A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human
A mechanistic model of amyloid beta production, degradation, and distribution was constructed for mouse, monkey, and human, calibrated and externally verified across multiple datasets. Simulations of single‐dose avagacestat treatment demonstrate that the Aβ(42) brain inhibition may exceed that in ce...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658289/ https://www.ncbi.nlm.nih.gov/pubmed/28571112 http://dx.doi.org/10.1002/psp4.12211 |
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author | Karelina, T Demin, O Nicholas, T Lu, Y Duvvuri, S Barton, HA |
author_facet | Karelina, T Demin, O Nicholas, T Lu, Y Duvvuri, S Barton, HA |
author_sort | Karelina, T |
collection | PubMed |
description | A mechanistic model of amyloid beta production, degradation, and distribution was constructed for mouse, monkey, and human, calibrated and externally verified across multiple datasets. Simulations of single‐dose avagacestat treatment demonstrate that the Aβ(42) brain inhibition may exceed that in cerebrospinal fluid (CSF). The dose that achieves 50% CSF Aβ(40) inhibition for humans (both healthy and with Alzheimer's disease (AD)) is about 1 mpk, one order of magnitude lower than for mouse (10 mpk), mainly because of differences in pharmacokinetics. The predicted maximal percent of brain Aβ(42) inhibition after single‐dose avagacestat is higher for AD subjects (about 60%) than for healthy individuals (about 45%). The probability of achieving a normal physiological level for Aβ(42) in brain (1 nM) during multiple avagacestat dosing can be increased by using a dosing regimen that achieves higher exposure. The proposed model allows prediction of brain pharmacodynamics for different species given differing dosing regimens. |
format | Online Article Text |
id | pubmed-5658289 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-56582892017-10-27 A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human Karelina, T Demin, O Nicholas, T Lu, Y Duvvuri, S Barton, HA CPT Pharmacometrics Syst Pharmacol Original Articles A mechanistic model of amyloid beta production, degradation, and distribution was constructed for mouse, monkey, and human, calibrated and externally verified across multiple datasets. Simulations of single‐dose avagacestat treatment demonstrate that the Aβ(42) brain inhibition may exceed that in cerebrospinal fluid (CSF). The dose that achieves 50% CSF Aβ(40) inhibition for humans (both healthy and with Alzheimer's disease (AD)) is about 1 mpk, one order of magnitude lower than for mouse (10 mpk), mainly because of differences in pharmacokinetics. The predicted maximal percent of brain Aβ(42) inhibition after single‐dose avagacestat is higher for AD subjects (about 60%) than for healthy individuals (about 45%). The probability of achieving a normal physiological level for Aβ(42) in brain (1 nM) during multiple avagacestat dosing can be increased by using a dosing regimen that achieves higher exposure. The proposed model allows prediction of brain pharmacodynamics for different species given differing dosing regimens. John Wiley and Sons Inc. 2017-08-10 2017-10 /pmc/articles/PMC5658289/ /pubmed/28571112 http://dx.doi.org/10.1002/psp4.12211 Text en © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Articles Karelina, T Demin, O Nicholas, T Lu, Y Duvvuri, S Barton, HA A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human |
title | A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human |
title_full | A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human |
title_fullStr | A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human |
title_full_unstemmed | A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human |
title_short | A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human |
title_sort | translational systems pharmacology model for aβ kinetics in mouse, monkey, and human |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658289/ https://www.ncbi.nlm.nih.gov/pubmed/28571112 http://dx.doi.org/10.1002/psp4.12211 |
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