PT  - JOURNAL ARTICLE
AU  - Yasong Lu
AU  - David Riddell
AU  - Eva Hajos-Korcsok
AU  - Kelly Bales
AU  - Kathleen M. Wood
AU  - Charles E. Nolan
AU  - Ashley E. Robshaw
AU  - Liming Zhang
AU  - Louis Leung
AU  - Stacey L. Becker
AU  - Elaine Tseng
AU  - Jason Barricklow
AU  - Emily H. Miller
AU  - Sarah Osgood
AU  - Brian T. O'Neill
AU  - Michael A. Brodney
AU  - Douglas S. Johnson
AU  - Martin Pettersson
TI  - Cerebrospinal Fluid Amyloid-β (Aβ) as an Effect Biomarker for Brain Aβ Lowering Verified by Quantitative Preclinical Analyses
AID  - 10.1124/jpet.112.192625
DP  - 2012 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 366--375
VI  - 342
IP  - 2
4099  - http://jpet.aspetjournals.org/content/342/2/366.short
4100  - http://jpet.aspetjournals.org/content/342/2/366.full
SO  - J Pharmacol Exp Ther2012 Aug 01; 342
AB  - 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.