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CPT Pharmacometrics Syst Pharmacol. 2017 Oct;6(10):666-675. doi: 10.1002/psp4.12211. Epub 2017 Aug 10.

A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human.

Author information

1
Institute for Systems Biology, Moscow, Russia.
2
Pfizer, Groton, CT, USA.

Abstract

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 Aβ42 brain inhibition may exceed that in cerebrospinal fluid (CSF). The dose that achieves 50% CSF Aβ40 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 Aβ42 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 Aβ42 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.

PMID:
28571112
PMCID:
PMC5658289
DOI:
10.1002/psp4.12211
[Indexed for MEDLINE]
Free PMC Article

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