Biomarkers.

Area of Science:

• Pharmacokinetics and Pharmacodynamics
• Neurodegenerative Diseases
• Drug Development

Background:

• Physiologically based pharmacokinetic (PBPK) models simulate antibody therapeutics' disposition in the central nervous system (CNS), including cerebrospinal (CSF) and interstitial fluid (ISF).
• These models can predict amyloid aggregation dynamics and treatment effects.
• Donanemab, an IgG1 antibody targeting N3pG beta-amyloid, is indicated for early symptomatic Alzheimer's disease (AD).

Purpose of the Study:

• To establish a donanemab PBPK model integrated with an amyloid plaque lifecycle model.
• To identify target ISF concentrations for donanemab.
• To predict the impact of donanemab dosing regimens on brain amyloid plaque levels.

Main Methods:

• A longitudinal natural life cycle model of amyloid aggregation was developed for early symptomatic AD participants.
• The model evaluated donanemab's impact on amyloid aggregation at targeted ISF concentrations.
• Data from Phase 1, 2, and 3 studies (N=2560) of donanemab in early symptomatic AD were analyzed.

Main Results:

• Age and APOE4 genotype significantly influence amyloid aggregation, with declines in CSF/ISF Aβ42 and plasma Aβ42/Aβ40 ratio around age 60.
• Amyloid plaque levels increase around age 60, saturating at higher ages, with earlier onset in APOE4 carriers.
• Donanemab treatment in early symptomatic AD patients (mean age 73.2) achieved robust amyloid plaque reduction when maintaining serum concentrations >15 µg/mL, with corresponding CSF and ISF levels.

Conclusions:

• Understanding CNS disposition of amyloid-targeting agents enhances comprehension of therapeutic ISF concentrations.
• The donanemab PBPK/amyloid plaque model provides a tool for optimizing dosing strategies.
• This modeling approach supports the development of effective treatments for Alzheimer's disease.