Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Karelina, T, Demin, O, Nicholas, T, Lu, Y, Duvvuri, S, Barton, HA
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
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
_version_ 1783273961193209856
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
work_keys_str_mv AT karelinat atranslationalsystemspharmacologymodelforabkineticsinmousemonkeyandhuman
AT demino atranslationalsystemspharmacologymodelforabkineticsinmousemonkeyandhuman
AT nicholast atranslationalsystemspharmacologymodelforabkineticsinmousemonkeyandhuman
AT luy atranslationalsystemspharmacologymodelforabkineticsinmousemonkeyandhuman
AT duvvuris atranslationalsystemspharmacologymodelforabkineticsinmousemonkeyandhuman
AT bartonha atranslationalsystemspharmacologymodelforabkineticsinmousemonkeyandhuman
AT karelinat translationalsystemspharmacologymodelforabkineticsinmousemonkeyandhuman
AT demino translationalsystemspharmacologymodelforabkineticsinmousemonkeyandhuman
AT nicholast translationalsystemspharmacologymodelforabkineticsinmousemonkeyandhuman
AT luy translationalsystemspharmacologymodelforabkineticsinmousemonkeyandhuman
AT duvvuris translationalsystemspharmacologymodelforabkineticsinmousemonkeyandhuman
AT bartonha translationalsystemspharmacologymodelforabkineticsinmousemonkeyandhuman