Publication Date:
2013-06-14
Description:
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 [(4 S ,4 a ' S ,10 a ' 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(1 H )-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(1 H )-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 (A β ) in the plasma and cerebrospinal fluid (CSF), and secreted APP β (sAPP β ) and secreted APP α (sAPP α ) 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 A β and CSF A β , sAPP α , and sAPP β 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 IC 50 of 0.0033 μ M and 0.065 μ M, respectively. These differences in CSF and free plasma IC 50 suggest that different mechanisms are involved in A β 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 A β , sAPP β , and sAPP α in the CSF, and A β 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.
Print ISSN:
0090-9556
Electronic ISSN:
1521-009X
Topics:
Chemistry and Pharmacology
,
Medicine
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