Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ₄₀ and Aβ₄₂ following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers

Abstract

Modulating deposition of Aβ-containing plaques in the brain may be beneficial in treating Alzheimer's disease. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors have been shown to reduce Aβ in plasma and CSF in healthy volunteers. In this study safety, pharmacokinetics and pharmacodynamics that is reduction of the plasma biomarkers Aβ40 and Aβ42 , of the BACE1 inhibitor AZD3839 were evaluated. Single oral ascending doses (1-300 mg) 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 Aβ40 and Aβ42 in plasma with estimated potencies (EC50 ) of 46 and 59 nM, 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 20 milliseconds at 300 mg). In conclusion, AZD3839 reduced plasma Aβ40 and Aβ42 , 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.

Prediction and Modeling of Effects on the QTc Interval for Clinical Safety Margin Assessment, Based on Single-Ascending-Dose Study Data with AZD3839

“…In spite of a high degree of BSV in PK in humans (Quartino et al, 2014), a clear dose-dependent increase in QTc interval prolongation was demonstrated in the SAD study.…”

“…A 20% average reduction in plasma Ab 1-42 was achieved by doses of 110 mg twice daily or 8 mg every hour, yielding steady-state C max of 400 and 45 nM, respectively (Quartino et al, 2014). At these concentrations, Fig.…”

“…More detailed information regarding the study design PK of AZD3839, effects on the plasma efficacy biomarkers Ab 1-40 and Ab 1-42 , and PK/PD relationship are presented elsewhere (Quartino et al, 2014).…”

“…The relative bioavailability for AZD3839 was found to be nonlinear and resulted in higher than dose-proportional increase in drug exposure with dose. A free fraction of 3.6% was used to convert total to free concentrations in humans (Quartino et al, 2014).…”

“…To quantify the concentration-response relationship in dog and healthy subjects, a population modeling approach was used. The population PK model describing the total plasma concentrations of AZD3839 in humans is presented elsewhere (Quartino et al, 2014). In the dog, the total concentrations of AZD3839 were well characterized by a two-compartment model with first-order absorption and linear elimination.…”