Mechanistic pharmacokinetic-pharmacodynamic modeling of BACE1 inhibition in monkeys: development of a predictive model for amyloid precursor protein processing.

Liu X, Wong H, Scearce-Levie K, Watts R, Coraggio M, Shin Y, Peng K, Wildsmith K, Atwal J, Mango J, Schauer S, Regal K, Hunt K, Thomas A, Siu M, Lyssikatos J, Deshmukh G, Hop C.
Journal   Drug Metab Dispos
Species  
Analytes Measured   Abeta 40 , APP
Matrix Tested   Cerebrospinal fluid (CSF), plasma
Year   2013
Volume  
Page Numbers  
Application   Alzheimers
Abstract
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 and GNE-892, 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 following 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 following 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 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.

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