2008 - Marseille - France

PAGE 2008: Applications- CNS
Monica Simeoni

Modelling beta amyloid system: sensitivity analysis at steady state and in dynamic conditions.

M. Simeoni(1), C. Chen(1), P. Dua(2), R.E. Oliver-Willwong (1), D. J. Austin(1)

(1)Clinical Pharmacology Modelling and Simulation, GSK, Greenford/Harlow, UK, (2) Neurosciences CEDD, GSK, Harlow, UK

Objectives: Alzheimer disease (AD) is the most common form of senile dementia. Amyloid beta peptide in the brain is a hallmark of this pathology and is related with cognitive decline, neurotoxicity and the formation of neurofibrillary tangles. A growing number of drugs are being tested in order to reduce the amyloid burden via different mechanisms and/or sites of action. The inaccessibility of direct measurement in the brain constitutes a limitation for the optimal design of the clinical studies. We propose a compartmental model that can be used to anticipate the profile of the peptide in the different sites (periphery and central nervous system). We then consider the effects of different mechanisms of action on the various peptide exchange rates via simulation analysis for novel drugs of interest.

Methods and Results: This is a methodology work. A compartmental model was used to represent the brain, plasma and CSF amyloid pools. Given the absence of a precise knowledge of all the rates of exchange in any one animal species, we studied the impact of the unknown rates on the system at steady-state. We then applied the various novel drug mechanisms in the model to look at the predicted steady-state efficacy.

Conclusions: Assuming that amyloid beta fluxes are linear, we predict a number of preferential pathways for reduction of the amyloid beta in the brain. Moreover, some exchange rates in the system can have a significant impact on the efficacy of the drug action. The true biological system may present additional nonlinearities that need further investigation and will be included in the mathematical model.

Reference: PAGE 17 (2008) Abstr 1396 [www.page-meeting.org/?abstract=1396]
Poster: Applications- CNS