RT Journal Article
SR Electronic
T1 Mechanistic Pharmacokinetic-Pharmacodynamic Modeling of BACE1 Inhibition in Monkeys: Development of a Predictive Model for Amyloid Precursor Protein Processing
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1319
OP 1328
DO 10.1124/dmd.112.050864
VO 41
IS 7
A1 Xingrong Liu
A1 Harvey Wong
A1 Kimberly Scearce-Levie
A1 Ryan J. Watts
A1 Melis Coraggio
A1 Young G. Shin
A1 Kun Peng
A1 Kristin R. Wildsmith
A1 Jasvinder K. Atwal
A1 Jason Mango
A1 Stephen P. Schauer
A1 Kelly Regal
A1 Kevin W. Hunt
A1 Allen A. Thomas
A1 Michael Siu
A1 Joseph Lyssikatos
A1 Gauri Deshmukh
A1 Cornelis E. C. A. Hop
YR 2013
UL http://dmd.aspetjournals.org/content/41/7/1319.abstract
AB This study was conducted to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of two novel inhibitors of β-site amyloid precursor protein (APP)–cleaving enzyme (BACE1), GNE-629 [(4S,4a′S,10a′S)-2-amino-8′-(2-fluoropyridin-3-yl)-1-methyl-3′,4′,4a′,10a′-tetrahydro-1′H-spiro[imidazole-4,10′-pyrano[4,3-b]chromen]-5(1H)-one] and GNE-892 [(R)-2-amino-1,3′,3′-trimethyl-7′-(pyrimidin-5-yl)-3′,4′-dihydro-2′H-spiro[imidazole-4,1′-naphthalen]-5(1H)-one], and to develop a PK-PD model to predict in vivo effects based solely on in vitro activity and PK. GNE-629 and GNE-892 concentrations and PD biomarkers including amyloid β (Aβ) in the plasma and cerebrospinal fluid (CSF), and secreted APPβ (sAPPβ) and secreted APPα (sAPPα) in the CSF were measured after a single oral administration of GNE-629 (100 mg/kg) or GNE-892 (30 or 100 mg/kg) in cynomolgus monkeys. A mechanistic PK-PD model was developed to simultaneously characterize the plasma Aβ and CSF Aβ, sAPPα, and sAPPβ using GNE-629 in vivo data. This model was used to predict the in vivo effects of GNE-892 after adjustments based on differences in in vitro cellular activity and PK. The PK-PD model estimated GNE-629 CSF and free plasma IC50 of 0.0033 μM and 0.065 μM, respectively. These differences in CSF and free plasma IC50 suggest that different mechanisms are involved in Aβ formation in these two compartments. The predicted in vivo effects for GNE-892 using the PK-PD model were consistent with the observed data. In conclusion, a PK-PD model was developed to mechanistically describe the effects of BACE1 inhibition on Aβ, sAPPβ, and sAPPα in the CSF, and Aβ in the plasma. This model can be used to prospectively predict in vivo effects of new BACE1 inhibitors using just their in vitro activity and PK data.