title: Quantitative pharmacokinetic/pharmacodynamic analyses suggest that the 129/SVE mouse is a suitable preclinical pharmacology model for identifying small-molecule γ-secretase inhibitors.
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.
authors.affiliation: Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA Yasong.Lu@pfizer.com
authors.forename: Yasong
authors.initials: Y
authors.lastname: Lu
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.forename: Charles E
authors.initials: CE
authors.lastname: Nolan
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Becker
authors.forename: Kevin
authors.initials: K
authors.lastname: Atchison
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Robshaw
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Pustilnik
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Osgood
authors.forename: Emily H
authors.initials: EH
authors.lastname: Miller
authors.forename: Antonia F
authors.initials: AF
authors.lastname: Stepan
authors.forename: Chakrapani
authors.initials: C
authors.lastname: Subramanyam
authors.forename: Ivan
authors.initials: I
authors.lastname: Efremov
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hallgren
authors.forename: David
authors.initials: D
authors.lastname: Riddell
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001381:Azepines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D023421:Models, Animal; D010069:Oxadiazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D054852:Small Molecule Libraries; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001381:Azepines; C554092:BMS 708163; D004791:Enzyme Inhibitors; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D010069:Oxadiazoles; D054852:Small Molecule Libraries; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine