TY - JOUR
T1 - Mechanistic Pharmacokinetic-Pharmacodynamic Modeling of BACE1 Inhibition in Monkeys
T2 - Development of a Predictive Model for Amyloid Precursor Protein Processings
AU - Liu, Xingrong
AU - Wong, Harvey
AU - Scearce-Levie, Kimberly
AU - Watts, Ryan J.
AU - Coraggio, Melis
AU - Shin, Young G.
AU - Peng, Kun
AU - Wildsmith, Kristin R.
AU - Atwal, Jasvinder K.
AU - Mango, Jason
AU - Schauer, Stephen P.
AU - Regal, Kelly
AU - Hunt, Kevin W.
AU - Thomas, Allen A.
AU - Siu, Michael
AU - Lyssikatos, Joseph
AU - Deshmukh, Gauri
AU - Hop, Cornelis E.C.A.
PY - 2013/7
Y1 - 2013/7
N2 - 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,4a9S,10a9S)-2-amino-89-(2- fluoropyridin-3-yl)-1-methyl-39,49,4a9,10a9- tetrahydro-19H-spiro[imidazole-4, 109-pyrano[4,3-b]chromen]- 5(1H)-one] and GNE-892 [(R)-2-amino-1,39,39- trimethyl-79-(pyrimidin- 5-yl)-39,49-dihydro-29H-spiro[imidazole-4,19- 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 b (Ab) in the plasma and cerebrospinal fluid (CSF), and secreted APPb (sAPPb) and secreted APPa (sAPPa) 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 Ab and CSF Ab, sAPPa, and sAPPb 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 mM and 0.065 mM, respectively. These differences in CSF and free plasma IC50 suggest that different mechanisms are involved in Ab 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 Ab, sAPPb, and sAPPa in the CSF, and Ab 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.
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,4a9S,10a9S)-2-amino-89-(2- fluoropyridin-3-yl)-1-methyl-39,49,4a9,10a9- tetrahydro-19H-spiro[imidazole-4, 109-pyrano[4,3-b]chromen]- 5(1H)-one] and GNE-892 [(R)-2-amino-1,39,39- trimethyl-79-(pyrimidin- 5-yl)-39,49-dihydro-29H-spiro[imidazole-4,19- 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 b (Ab) in the plasma and cerebrospinal fluid (CSF), and secreted APPb (sAPPb) and secreted APPa (sAPPa) 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 Ab and CSF Ab, sAPPa, and sAPPb 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 mM and 0.065 mM, respectively. These differences in CSF and free plasma IC50 suggest that different mechanisms are involved in Ab 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 Ab, sAPPb, and sAPPa in the CSF, and Ab 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.
UR - http://www.scopus.com/inward/record.url?scp=84879101656&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879101656&partnerID=8YFLogxK
U2 - 10.1124/dmd.112.050864
DO - 10.1124/dmd.112.050864
M3 - Article
C2 - 23584887
AN - SCOPUS:84879101656
VL - 41
SP - 1319
EP - 1328
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
SN - 0090-9556
IS - 7
ER -