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Research ArticleDrug Discovery and Translational Medicine

Cerebrospinal Fluid Amyloid-β (Aβ) as an Effect Biomarker for Brain Aβ Lowering Verified by Quantitative Preclinical Analyses

Yasong Lu, David Riddell, Eva Hajos-Korcsok, Kelly Bales, Kathleen M. Wood, Charles E. Nolan, Ashley E. Robshaw, Liming Zhang, Louis Leung, Stacey L. Becker, Elaine Tseng, Jason Barricklow, Emily H. Miller, Sarah Osgood, Brian T. O'Neill, Michael A. Brodney, Douglas S. Johnson and Martin Pettersson
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 366-375; DOI: https://doi.org/10.1124/jpet.112.192625
Yasong Lu
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David Riddell
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Eva Hajos-Korcsok
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Kelly Bales
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Kathleen M. Wood
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Charles E. Nolan
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Ashley E. Robshaw
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Liming Zhang
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Louis Leung
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Stacey L. Becker
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Elaine Tseng
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Jason Barricklow
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Emily H. Miller
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Sarah Osgood
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Brian T. O'Neill
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Michael A. Brodney
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Douglas S. Johnson
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Martin Pettersson
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Abstract

Reducing the generation of amyloid-β (Aβ) in the brain via inhibition of β-secretase or inhibition/modulation of γ-secretase has been pursued as a potential disease-modifying treatment for Alzheimer's disease. For the discovery and development of β-secretase inhibitors (BACEi), γ-secretase inhibitors (GSI), and γ-secretase modulators (GSM), Aβ in cerebrospinal fluid (CSF) has been presumed to be an effect biomarker for Aβ lowering in the brain. However, this presumption is challenged by the lack of quantitative understanding of the relationship between brain and CSF Aβ lowering. In this study, we strived to elucidate how the intrinsic pharmacokinetic (PK)/pharmacodynamic (PD) relationship for CSF Aβ lowering is related to that for brain Aβ through quantitative modeling of preclinical data for numerous BACEi, GSI, and GSM across multiple species. Our results indicate that the intrinsic PK/PD relationship in CSF is predictive of that in brain, at least in the postulated pharmacologically relevant range, with excellent consistency across mechanisms and species. As such, the validity of CSF Aβ as an effect biomarker for brain Aβ lowering is confirmed preclinically. Meanwhile, we have been able to reproduce the dose-dependent separation between brain and CSF effect profiles using simulations. We further discuss the implications of our findings to drug discovery and development with regard to preclinical PK/PD characterization and clinical prediction of Aβ lowering in the brain.

Footnotes

  • This study was supported by Pfizer Worldwide Research and Development, Pfizer Inc.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.192625.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    AD
    Alzheimer's disease
    Aβ
    amyloid-β
    BACEi
    beta secretase inhibitor(s)
    GSI
    γ-secretase inhibitor(s)
    GSM
    γ-secretase modulator(s)
    CSF
    cerebrospinal fluid
    PK
    pharmacokinetic
    PD
    pharmacodynamic
    LY2811376
    (4S)-4-(2,4-difluoro-5-pyrimidin-5-ylphenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine
    BACE-A
    N-{3-[(4aS,7aS)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]-4-fluorophenyl}-5-fluoropyridine-2-carboxamide
    E2012
    (S,E)-1-(1-(4-fluorophenyl)ethyl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidin-2-one
    GSM-A
    (S,E)-2-(2-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)vinyl)-8-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
    PBS-T
    phosphate-buffered saline containing 0.05% Tween 20
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry.

  • Received January 31, 2012.
  • Accepted April 27, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 2
1 Aug 2012
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Research ArticleDrug Discovery and Translational Medicine

CSF Aβ as an Effect Biomarker for Brain Aβ Lowering

Yasong Lu, David Riddell, Eva Hajos-Korcsok, Kelly Bales, Kathleen M. Wood, Charles E. Nolan, Ashley E. Robshaw, Liming Zhang, Louis Leung, Stacey L. Becker, Elaine Tseng, Jason Barricklow, Emily H. Miller, Sarah Osgood, Brian T. O'Neill, Michael A. Brodney, Douglas S. Johnson and Martin Pettersson
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 366-375; DOI: https://doi.org/10.1124/jpet.112.192625

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Research ArticleDrug Discovery and Translational Medicine

CSF Aβ as an Effect Biomarker for Brain Aβ Lowering

Yasong Lu, David Riddell, Eva Hajos-Korcsok, Kelly Bales, Kathleen M. Wood, Charles E. Nolan, Ashley E. Robshaw, Liming Zhang, Louis Leung, Stacey L. Becker, Elaine Tseng, Jason Barricklow, Emily H. Miller, Sarah Osgood, Brian T. O'Neill, Michael A. Brodney, Douglas S. Johnson and Martin Pettersson
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 366-375; DOI: https://doi.org/10.1124/jpet.112.192625
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