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Research ArticleDrug Discovery and Translational Medicine

Quantitative Pharmacokinetic/Pharmacodynamic Analyses Suggest That the 129/SVE Mouse Is a Suitable Preclinical Pharmacology Model for Identifying Small-Molecule γ-Secretase Inhibitors

Yasong Lu, Liming Zhang, Charles E. Nolan, Stacey L. Becker, Kevin Atchison, Ashley E. Robshaw, Leslie R. Pustilnik, Sarah M. Osgood, Emily H. Miller, Antonia F. Stepan, Chakrapani Subramanyam, Ivan Efremov, Andrew J. Hallgren and David Riddell
Journal of Pharmacology and Experimental Therapeutics December 2011, 339 (3) 922-934; DOI: https://doi.org/10.1124/jpet.111.186791
Yasong Lu
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Liming Zhang
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Charles E. Nolan
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Stacey L. Becker
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Kevin Atchison
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Ashley E. Robshaw
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Leslie R. Pustilnik
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Sarah M. Osgood
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Emily H. Miller
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Antonia F. Stepan
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Chakrapani Subramanyam
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Ivan Efremov
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Andrew J. Hallgren
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David Riddell
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Abstract

Alzheimer's disease (AD) poses a serious public health threat to the United States. Disease-modifying drugs slowing AD progression are in urgent need, but they are still unavailable. According to the amyloid cascade hypothesis, inhibition of β- or γ-secretase, key enzymes for the production of amyloid β (Aβ), may be viable mechanisms for the treatment of AD. For the discovery of γ-secretase inhibitors (GSIs), the APP-overexpressing Tg2576 mouse has been the preclinical model of choice, in part because of the ease of detection of Aβ species in its brain, plasma, and cerebrospinal fluid (CSF). Some biological observations and practical considerations, however, argue against the use of the Tg2576 mouse. We reasoned that an animal model would be suitable for GSI discovery if the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of a compound for Aβ lowering in this model is predictive of that in human. In this study, we assessed whether the background 129/SVE strain is a suitable preclinical pharmacology model for identifying new GSIs by evaluating the translatability of the intrinsic PK/PD relationships for brain and CSF Aβ across the Tg2576 and 129/SVE mouse and human. Using semimechanistically based PK/PD modeling, our analyses indicated that the intrinsic PK/PD relationship for brain Aβx-42 and CSF Aβx-40 in the 129/SVE mouse is indicative of that for human CSF Aβ. This result, in conjunction with practical considerations, strongly suggests that the 129/SVE mouse is a suitable model for GSI discovery. Concurrently, the necessity and utilities of PK/PD modeling for rational interpretation of Aβ data are established.

Footnotes

  • This work was supported by Pfizer Worldwide Research and Development.

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

    doi:10.1124/jpet.111.186791.

  • ↵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
    APP
    amyloid precursor protein
    AUC
    area under the concentration curve
    Cbu
    free brain concentration
    CSF
    cerebrospinal fluid
    GSI
    γ-secretase inhibitor
    IVIVC
    in vitro-in vivo potency correlation
    PK
    pharmacokinetic
    PD
    pharmacodynamic
    DMSO
    dimethyl sulfoxide
    ELISA
    enzyme-linked immunosorbent assay
    PBS-T
    phosphate-buffered saline containing 0.05% Tween 20
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    BMS-708163
    (2R)-2-[N-[(4-chlorophenyl)sulfonyl]-N-[2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl]amino]-5,5,5-trifluoropentanamide
    PF-6239574
    (R)-4-cyclopropyl-8-fluoro-5-((5-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline
    Imax
    maximum inhibition of Aβ generation
    γ
    Hill coefficient
    IC50
    concentration that causes 50% of maximum inhibition of Aβ generation
    kout
    Aβ clearance rate constant.

  • Received August 9, 2011.
  • Accepted September 15, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 3
1 Dec 2011
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Research ArticleDrug Discovery and Translational Medicine

129/SVE Mouse Is a Suitable Animal Model for GSI Discovery

Yasong Lu, Liming Zhang, Charles E. Nolan, Stacey L. Becker, Kevin Atchison, Ashley E. Robshaw, Leslie R. Pustilnik, Sarah M. Osgood, Emily H. Miller, Antonia F. Stepan, Chakrapani Subramanyam, Ivan Efremov, Andrew J. Hallgren and David Riddell
Journal of Pharmacology and Experimental Therapeutics December 1, 2011, 339 (3) 922-934; DOI: https://doi.org/10.1124/jpet.111.186791

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Research ArticleDrug Discovery and Translational Medicine

129/SVE Mouse Is a Suitable Animal Model for GSI Discovery

Yasong Lu, Liming Zhang, Charles E. Nolan, Stacey L. Becker, Kevin Atchison, Ashley E. Robshaw, Leslie R. Pustilnik, Sarah M. Osgood, Emily H. Miller, Antonia F. Stepan, Chakrapani Subramanyam, Ivan Efremov, Andrew J. Hallgren and David Riddell
Journal of Pharmacology and Experimental Therapeutics December 1, 2011, 339 (3) 922-934; DOI: https://doi.org/10.1124/jpet.111.186791
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