title: Cerebrospinal fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative preclinical analyses.
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.
authors.affiliation: MS#220-4546, 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: David
authors.initials: D
authors.lastname: Riddell
authors.forename: Eva
authors.initials: E
authors.lastname: Hajos-Korcsok
authors.forename: Kelly
authors.initials: K
authors.lastname: Bales
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Wood
authors.forename: Charles E
authors.initials: CE
authors.lastname: Nolan
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Robshaw
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.forename: Louis
authors.initials: L
authors.lastname: Leung
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Becker
authors.forename: Elaine
authors.initials: E
authors.lastname: Tseng
authors.forename: Jason
authors.initials: J
authors.lastname: Barricklow
authors.forename: Emily H
authors.initials: EH
authors.lastname: Miller
authors.forename: Sarah
authors.initials: S
authors.lastname: Osgood
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brodney
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Johnson
authors.forename: Martin
authors.initials: M
authors.lastname: Pettersson
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000134:cerebrospinal fluid / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002555:Cerebrospinal Fluid / Q000737:chemistry; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases