Population pharmacokinetic modelling of NS2330 (tesofensine) and its major metabolite in patients with Alzheimer's disease.

Aims: To develop a population pharmacokinetic model for NS2330 and its major metabolite M1 based on data from a 14 week proof of concept study in patients with Alzheimer's disease, and to identify covariates that might influence the pharmacokinetic characteristics of the drug and/or its metabolite.

Methods: Plasma data from 320 subjects undergoing multiple oral dosing, and consisting of 1969 NS2330 and 1714 metabolite concentrations were fitted simultaneously using NONMEM.

Results: Plasma concentration-time profiles of NS2330 and M1 were best described by one-compartment models with first-order elimination for both compounds.

Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of A beta 42 in patients with Alzheimer's disease.

The amyloid beta-peptides A beta 40 and A beta 42 are highly amyloidogenic constituents of brain beta-amyloid plaques in Alzheimer's disease (AD). Lowering their formation may be achieved by modulating the activities of proteases that cleave the amyloid precursor protein (A beta PP), including alpha- beta-, and gamma-secretases. Talsaclidine is a functionally selective muscarinic m1 agonist that stimulates non-amyloidogenic alpha-secretase processing in vitro.