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 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.