Application of systems pharmacology modeling of age-dependent aggregation of amyloid beta to possible pharmacological targets in Alzheimer’s disease in order to identify the optimal design of clinical trials

Aim of the project:

To identify optimal potency/exposure of the modulators for amyloid beta production/clearance in clinical trials.

Results:

A systems pharmacology model of amyloid beta aggregation in vivo was developed to characterize the formation, oligomerization, aggregation, disaggregation, and clearance of amyloid beta species in the brain. Aggregation and oligomerization parameters were fit to postmortem autopsy data in healthy subjects and Alzheimer’s disease patients. Amyloid beta PK parameters were obtained by allometric scaling of mouse data. Longitudinal simulations were compared to PET-PiB data to further verify the model. Simulations depicting pharmacological intervention directed toward inhibition of amyloid beta synthesis or increased amyloid beta clearance were conducted. Based upon the simulated pharmacological interventions, the magnitude of drug effects, duration of therapy, and initial population age are related to overall outcome. Therapies with minimal to moderate effects on synthesis or clearance would require long trial durations (> 5 years) to observe an effect.

Initiator of the project:

Pfizer

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