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CPT Pharmacometrics Syst Pharmacol. 2017 Oct;6(10):676-685. doi: 10.1002/psp4.12249. Epub 2017 Sep 28.

Studying the Progression of Amyloid Pathology and Its Therapy Using Translational Longitudinal Model of Accumulation and Distribution of Amyloid Beta.

Author information

1
InSysBio, Moscow, Russia.
2
Pfizer, Cambridge, MA, USA.
3
Pfizer, Groton, CT, USA.

Abstract

Long-term effects of amyloid targeted therapy can be studied using a mechanistic translational model of amyloid beta (Aβ) distribution and aggregation calibrated on published data in mouse and human species. Alzheimer disease (AD) pathology is modeled utilizing age-dependent pathological evolution for rate constants and several variants of explicit functions for Aβ toxicity influencing cognitive outcomes (Adas-cog). Preventive Aβ targeted therapies were simulated to minimize the Aβ difference from healthy physiological levels. Therapeutic targeted simulations provided similar predictions for mouse and human studies. Our model predicts that: (1) at least 1 year (2 years for preclinical AD) of treatment is needed to observe cognitive effects; (2) under the hypothesis with functional importance of Aβ, a 15% decrease in Aβ (using an imaging biomarker) is related to 15-20% cognition improvement by immunotherapy. Despite negative outcomes in clinical trials, Aβ continues to remain a prospective target demanding careful assessment of mechanistic effect and duration of trial design.

PMID:
28913897
PMCID:
PMC5658285
DOI:
10.1002/psp4.12249
[Indexed for MEDLINE]
Free PMC Article

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