Pharmaceutical Research

, Volume 31, Issue 3, pp 670–683 | Cite as

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

  • Juliette Janson
  • Susanna Eketjäll
  • Karin Tunblad
  • Fredrik Jeppsson
  • Stefan Von Berg
  • Camilla Niva
  • Ann-Cathrin Radesäter
  • Johanna Fälting
  • Sandra A. G. Visser
Research Paper



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.


Alzheimer’s disease amyloid β peptide brain cerebrospinal fluid pharmacokinetic-pharmacodynamic modeling 



Alzheimer’s disease


Amyloid precursor protein

Amyloid β peptide


β-site APP-cleaving enzyme 1


Cerebrospinal fluid


Coefficient of variation


Primary cortical neurons


Soluble N terminal fragment of APP



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.

Supplementary material

11095_2013_1189_MOESM1_ESM.pdf (72 kb)
Supplement 1 (PDF 71 kb)


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Juliette Janson
    • 1
  • Susanna Eketjäll
    • 2
  • Karin Tunblad
    • 1
  • Fredrik Jeppsson
    • 2
  • Stefan Von Berg
    • 3
  • Camilla Niva
    • 2
  • Ann-Cathrin Radesäter
    • 2
  • Johanna Fälting
    • 4
  • Sandra A. G. Visser
    • 5
  1. 1.Modeling & Simulation, DMPKInnovative Medicines CNSP AstraZenecaSödertäljeSweden
  2. 2.NeuroscienceInnovative Medicines CNSP AstraZenecaSödertäljeSweden
  3. 3.Medical ChemistryInnovative Medicines CNSP AstraZenecaSödertäljeSweden
  4. 4.Project ManagementInnovative Medicines CNSP AstraZenecaSödertäljeSweden
  5. 5.Global DMPK Centre of ExcellenceInnovative Medicines CNSP AstraZenecaSödertäljeSweden

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