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 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.