Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ40 and Aβ42 following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers. Issue 5 (26th May 2014)

• Record Type: Journal Article
• Authors: Quartino, Angelica; Huledal, Gunilla; Sparve, Erik; Lüttgen, Maria; Bueters, Tjerk; Karlsson, Pär; Olsson, Tina; Paraskos, Jonathan; Maltby, Justine; Claeson‐Bohnstedt, Kristina; Lee, Chi‐Ming; Alexander, Robert; Fälting, Johanna; Paulsson, Björn
• Is Part Of: Clinical pharmacology in drug development. Volume 3:Issue 5(2014:Sep./Oct.)
• Page Start: 396
• Page End: 405
• Publication Date: 2014-05-26
• Subjects: Drugs -- Testing -- Periodicals; Drug development -- Periodicals; Clinical pharmacology -- Periodicals; 615.580724
• DOI: 10.1002/cpdd.130
• Languages: English
• ISSNs: 2160-7648

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="cpdd130-sec-0001" sec-type="section"> <p>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 Aβ<sub>40</sub> and Aβ<sub>42</sub>, of the BACE1 inhibitor AZD3839 were evaluated.</p> <p>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 Aβ<sub>40</sub> and Aβ<sub>42</sub> in plasma with estimated potencies (EC<sub>50</sub>) 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).</p> <p>In conclusion, AZD3839 reduced plasma Aβ<sub>40</sub> and Aβ<sub>42</sub>, 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.</p> </sec> </abstract>