Population PKPD Modeling of BACE1 Inhibitor-Induced Reduction in Aβ Levels In Vivo and Correlation to In Vitro Potency in Primary Cortical Neurons from Mouse and Guinea Pig
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The aims were to quantify the in vivo time-course between the oral dose, the plasma and brain exposure and the inhibitory effect on Amyloid β (Aβ) in brain and cerebrospinal fluid, and to establish the correlation between in vitro and in vivo potency of novel β-secretase (BACE1) inhibitors.
BACE1-mediated inhibition of Aβ was quantified in in vivo dose- and/or time-response studies and in vitro in SH-SY5Y cells, N2A cells, and primary cortical neurons (PCN). An indirect response model with inhibition on Aβ production rate was used to estimate unbound in vivo IC 50 in a population pharmacokinetic-pharmacodynamic modeling approach.
Estimated in vivo inhibitory potencies varied between 1 and 1,000 nM. The turnover half-life of Aβ40 in brain was predicted to be 0.5 h in mouse and 1 h in guinea pig. An excellent correlation between PCN and in vivo potency was observed. Moreover, a strong correlation in potency was found between human SH-SY5Y cells and mouse PCN, being 4.5-fold larger in SH-SY5Y cells.
The strong in vivo-in vitro correlation increased the confidence in using human cell lines for screening and optimization of BACE1 inhibitors. This can optimize the design and reduce the number of preclinical in vivo effect studies.
KEY WORDSAlzheimer’s disease amyloid β peptide brain cerebrospinal fluid pharmacokinetic-pharmacodynamic modeling
Amyloid precursor protein
Amyloid β peptide
β-site APP-cleaving enzyme 1
Coefficient of variation
Primary cortical neurons
Soluble N terminal fragment of APP
ACKNOWLEDGMENTS AND DISCLOSURES
The authors would like to thank Eva Spennare for determining the fraction unbound in brain; Jenny Johansson for measuring the plasma protein binding; Hongmei Yan for collecting the data into the data-analysis sheet; Sveinn Briem and his team for performing the bioanalysis; Elin Lundkvist and Fredrik Olsson for supporting the in vitro experiments; and Kristina Eliason for supporting the in vivo experiments.
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