RT Journal Article
SR Electronic
T1 Cerebrospinal Fluid Amyloid-β (Aβ) as an Effect Biomarker for Brain Aβ Lowering Verified by Quantitative Preclinical Analyses
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 366
OP 375
DO 10.1124/jpet.112.192625
VO 342
IS 2
A1 Yasong Lu
A1 David Riddell
A1 Eva Hajos-Korcsok
A1 Kelly Bales
A1 Kathleen M. Wood
A1 Charles E. Nolan
A1 Ashley E. Robshaw
A1 Liming Zhang
A1 Louis Leung
A1 Stacey L. Becker
A1 Elaine Tseng
A1 Jason Barricklow
A1 Emily H. Miller
A1 Sarah Osgood
A1 Brian T. O'Neill
A1 Michael A. Brodney
A1 Douglas S. Johnson
A1 Martin Pettersson
YR 2012
UL http://jpet.aspetjournals.org/content/342/2/366.abstract
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.