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

Area of Science:

• Pharmacology
• Neuroscience
• Computational Biology

Background:

• Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) accumulation.
• Understanding Aβ dynamics and drug effects is crucial for developing effective treatments.
• Existing models may not fully capture species-specific Aβ pharmacodynamics.

Purpose of the Study:

• To develop and validate a mechanistic model for Aβ production, degradation, and distribution across species.
• To simulate the effects of avagacestat on Aβ levels in the brain and cerebrospinal fluid (CSF).
• To predict optimal dosing regimens for avagacestat to achieve therapeutic Aβ inhibition.

Main Methods:

• Construction of a mechanistic model for Aβ pharmacokinetics and pharmacodynamics.
• Calibration and external verification of the model using multiple datasets.
• In silico simulations of single-dose and multiple-dose avagacestat treatment.

Main Results:

• The model accurately describes Aβ dynamics in mouse, monkey, and human.
• Avagacestat's Aβ42 inhibition in the brain may exceed that in CSF.
• Lower doses are required for 50% Aβ40 inhibition in humans compared to mice due to pharmacokinetic differences.
• Higher maximal Aβ42 inhibition is predicted in AD subjects (60%) versus healthy individuals (45%).

Conclusions:

• The mechanistic model provides a valuable tool for predicting species-specific brain pharmacodynamics of Aβ-targeting drugs.
• Avagacestat demonstrates greater efficacy in AD subjects, supporting personalized treatment approaches.
• Optimized dosing regimens can enhance the probability of achieving normal Aβ levels in the brain.