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P3‐035: A Correlational Analysis of Exposure and Pharmacodynamic Effects of the Bace1 Inhibitor LY3202626 in PDAPP Mice Following Acute Oral Dosing
Author(s) -
Boggs Leonard N.,
May Patrick C.,
Yang Zhixiang,
Brier Richard A.,
Monk Scott A.,
Borders Anthony R.,
Winneroski Leonard L.,
Green Steven J.,
Mergott Dustin J.,
McKinzie David L.
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.1693
Subject(s) - hippocampal formation , pharmacodynamics , hippocampus , pharmacokinetics , dosing , pharmacology , oral administration , chemistry , medicine , endocrinology
Background: LY3202626 is a potent, freely CNS-penetrant small molecule BACE1 inhibitor in development for the treatment of Alzheimer’s disease (AD). Herein, we demonstrate strong pharmacokinetic / pharmacodynamic (PK/PD) relationships in PDAPP mice between central LY3202626 exposure and central (hippocampal and cortical brain tissue) BACE1 inhibition as determined by quantifying markers of amyloid precursor protein (APP) metabolism. Methods: In a dose response study, young female PDAPP mice (n1⁄46/group) were orally administered 0, 0.3, 1.0, or 3.0 mg LY3202626/kg and were sacrificed at 3 hr post-dose. In a separate time course study, young female PDAPP mice were sacrificed at 3, 6, 9, or 12 hours following a 3 mg LY3202626/kg oral dose. In all studies, LY3202626 concentrations were determined in plasma and brain samples by LC/MS/MS and concentrations of sAPPbeta, C99 and Abeta 1-X were determined in hippocampus and cortex using ELISA methodology. Results: Oral administration of LY3202626 to PDAPPmice produced dose-dependent reductions in brain Abeta, C99, and sAPPbeta with LY3202626 brain concentrations negatively-correlated with all three PD endpoints (r values > 0.56). Changes in each BACE1 biomarker were similar in the cortical and hippocampal brain regions (all r values > 0.90). In a timecourse study following a dose of 3 mg/kg LY3202626, free brain exposure over the 3-12 hour time-course study correlated well with hippocampal Abeta 1-X changes (r 1⁄4 0.60), indicating that the robust PK/PD relationship was maintained over time. All correlations were significant, with p-values <0.0001. Observed free (unbound) concentrations in brain and plasma across these studies suggest LY3202626 is highly brain penetrant in PDAPP mice. Conclusions:LY3202626 is a potent inhibitor of BACE1. Administration of LY3202626 results in significant changes in central biomarkers of BACE1 activity, and the magnitude of these changes correlate well with observed.