title: Mechanistic pharmacokinetic-pharmacodynamic modeling of BACE1 inhibition in monkeys: development of a predictive model for amyloid precursor protein processing.
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 [(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.
authors.affiliation: Genentech Inc., MS 41-2A, 1 DNA Way, South San Francisco, CA 94080, USA. liu.xingrong@gene.com
authors.forename: Xingrong
authors.initials: X
authors.lastname: Liu
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Watts
authors.forename: Melis
authors.initials: M
authors.lastname: Coraggio
authors.forename: Young G
authors.initials: YG
authors.lastname: Shin
authors.forename: Kun
authors.initials: K
authors.lastname: Peng
authors.forename: Kristin R
authors.initials: KR
authors.lastname: Wildsmith
authors.forename: Jasvinder K
authors.initials: JK
authors.lastname: Atwal
authors.forename: Jason
authors.initials: J
authors.lastname: Mango
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Schauer
authors.forename: Kelly
authors.initials: K
authors.lastname: Regal
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Hunt
authors.forename: Allen A
authors.initials: AA
authors.lastname: Thomas
authors.forename: Michael
authors.initials: M
authors.lastname: Siu
authors.forename: Joseph
authors.initials: J
authors.lastname: Lyssikatos
authors.forename: Gauri
authors.initials: G
authors.lastname: Deshmukh
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002853:Chromatography, Liquid; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008252:Macaca fascicularis; D008954:Models, Biological; D008969:Molecular Sequence Data; D011743:Pyrimidines / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D013843:Thiazines / Q000494:pharmacology
chemical_list: C584427:2-amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro(imidazole-4,1'-naphthalen)-5(1H)-one; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; C584426:GNE-629; D007093:Imidazoles; C569204:LY2811376; D011743:Pyrimidines; D013141:Spiro Compounds; D013843:Thiazines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human