RT Journal Article
SR Electronic
T1 Quantitative Pharmacokinetic/Pharmacodynamic Analyses Suggest That the 129/SVE Mouse Is a Suitable Preclinical Pharmacology Model for Identifying Small-Molecule γ-Secretase Inhibitors
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 922
OP 934
DO 10.1124/jpet.111.186791
VO 339
IS 3
A1 Lu, Yasong
A1 Zhang, Liming
A1 Nolan, Charles E.
A1 Becker, Stacey L.
A1 Atchison, Kevin
A1 Robshaw, Ashley E.
A1 Pustilnik, Leslie R.
A1 Osgood, Sarah M.
A1 Miller, Emily H.
A1 Stepan, Antonia F.
A1 Subramanyam, Chakrapani
A1 Efremov, Ivan
A1 Hallgren, Andrew J.
A1 Riddell, David
YR 2011
UL http://jpet.aspetjournals.org/content/339/3/922.abstract
AB 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.