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