The dynamics of Aß distribution after γ-secretase inhibitor treatment, as determined by experimental and modelling approaches in a wild type rat.

ABSTRACT

Inhibition of the enzyme(s) that produce the Amyloid beta (Aß) peptide, namely BACE and γ-secretase, is considered an attractive target for Alzheimer's disease therapy. However, the optimal pharmacokinetic-pharmacodynamic modelling method to describe the changes in Aß levels after drug treatment is unclear. In this study, turnover models were employed to describe Aß levels following treatment with the γ-secretase inhibitor RO5036450, in the wild type rat. Initially, Aß level changes in the brain, cerebral spinal fluid (CSF) and plasma were modeled as separate biological compartments, which allowed the estimation of a compound IC50 and Aß turnover. While the data were well described, the model did not take into consideration that the CSF pool of Aß most likely originates from the brain via the CSF drainage pathway. Therefore, a separate model was carried out, with the assumption that CSF Aß levels originated from the brain. The optimal model that described the data involved two brain Aß 40 sub-compartments, one with a rapid turnover, from which CSF Aß 40 is derived, and a second quasi-static pool of ~20%. Importantly, the estimated in vivo brain IC50 was in a good range of the in vitro IC50 (ratio, 1.4). In conclusion, the PK/PD models presented here are well suited for describing the temporal changes in Aß levels that occur after treatment with an Aß lowering drug, and identifying physiological parameters.