title: The dynamics of Aβ 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 (Aβ) 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 Aβ levels after drug treatment is unclear. In this study, turnover models were employed to describe Aβ levels following treatment with the γ-secretase inhibitor RO5036450, in the wild type rat. Initially, Aβ 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 Aβ turnover. While the data were well described, the model did not take into consideration that the CSF pool of Aβ most likely originates from the brain via the CSF drainage pathway. Therefore, a separate model was carried out, with the assumption that CSF Aβ levels originated from the brain. The optimal model that described the data involved two brain Aβ 40 sub-compartments, one with a rapid turnover, from which CSF Aβ 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 Aβ levels that occur after treatment with an Aβ lowering drug, and identifying physiological parameters.
authors.affiliation: Preclinical Modeling and Simulation and Preclinical CNS Research Departments, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Leon M
authors.initials: LM
authors.lastname: Tai
authors.forename: Helmut
authors.initials: H
authors.lastname: Jacobsen
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.forename: Alexander
authors.initials: A
authors.lastname: Flohr
authors.forename: Roland
authors.initials: R
authors.lastname: Jakob-Roetne
authors.forename: Antonello
authors.initials: A
authors.lastname: Caruso
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Grimm
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases