Population pharmacokinetic and pharmacodynamic analysis of plasma A[beta]40 and A[beta]42 following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers

Modulating deposition of A[beta]-containing plaques in the brain may be beneficial in treating Alzheimer's disease. [beta]-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors have been shown to reduce A[beta] in plasma and CSF in healthy volunteers. In this study safety, pharmacokinetics and pharmacodynamics that is reduction of the plasma biomarkers A[beta]40 and A[beta]42, of the BACE1 inhibitor AZD3839 were evaluated. Single oral ascending doses (1-300mg) of AZD3839 were administered to 54 young healthy volunteers in a randomized, double-blind, placebo-controlled study. The data was analyzed using non-linear mixed effects modeling. AZD3839 reduced A[beta]40 and A[beta]42 in plasma with estimated potencies (EC50) of 46 and 59nM, respectively, and a maximum effect of approximately 55%. This was in excellent agreement with the concentration-response relationships obtained in mouse and guinea pig. AZD3839 exposure displayed non-linear kinetics, described by a three-compartment model with a saturated binding compartment and an increase in bioavailability with dose. AZD3839 was safe, although, a dose-dependent QTcF prolongation was observed (mean 20milliseconds at 300mg). In conclusion, AZD3839 reduced plasma A[beta]40 and A[beta]42, demonstrating clinical peripheral proof of mechanism. Pre-clinical models were predictive for the effect of AZD3839 on the human plasma biomarker in a strictly quantitative manner.