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Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ 40 and Aβ 42 following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers
Author(s) -
Quartino Angelica,
Huledal Gunilla,
Sparve Erik,
Lüttgen Maria,
Bueters Tjerk,
Karlsson Pär,
Olsson Tina,
Paraskos Jonathan,
Maltby Justine,
ClaesonBohnstedt Kristina,
Lee ChiMing,
Alexander Robert,
Fälting Johanna,
Paulsson Björn
Publication year - 2014
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.130
Subject(s) - pharmacokinetics , pharmacodynamics , medicine , pharmacology , bioavailability , placebo , population , biomarker , pathology , chemistry , biochemistry , alternative medicine , environmental health
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 40 and Aβ 42 , 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 Aβ 40 and Aβ 42 in plasma with estimated potencies (EC 50 ) 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 Aβ 40 and Aβ 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.