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Population PKPD modeling of BACE1 inhibitor-induced reduction in Aβ levels in vivo and correlation to in vitro potency in primary cortical neurons from mouse and guinea pig
- Source :
- Pharmaceutical research. 31(3)
- Publication Year :
- 2013
-
Abstract
- The aims were to quantify the in vivo time-course between the oral dose, the plasma and brain exposure and the inhibitory effect on Amyloid β (Aβ) in brain and cerebrospinal fluid, and to establish the correlation between in vitro and in vivo potency of novel β-secretase (BACE1) inhibitors. BACE1-mediated inhibition of Aβ was quantified in in vivo dose- and/or time-response studies and in vitro in SH-SY5Y cells, N2A cells, and primary cortical neurons (PCN). An indirect response model with inhibition on Aβ production rate was used to estimate unbound in vivo IC 50 in a population pharmacokinetic-pharmacodynamic modeling approach. Estimated in vivo inhibitory potencies varied between 1 and 1,000 nM. The turnover half-life of Aβ40 in brain was predicted to be 0.5 h in mouse and 1 h in guinea pig. An excellent correlation between PCN and in vivo potency was observed. Moreover, a strong correlation in potency was found between human SH-SY5Y cells and mouse PCN, being 4.5-fold larger in SH-SY5Y cells. The strong in vivo-in vitro correlation increased the confidence in using human cell lines for screening and optimization of BACE1 inhibitors. This can optimize the design and reduce the number of preclinical in vivo effect studies.
- Subjects :
- Male
Population
Guinea Pigs
Pharmaceutical Science
Pharmacology
Biology
Inhibitory postsynaptic potential
Models, Biological
Cell Line
Guinea pig
Correlation
Mice
Cerebrospinal fluid
In vivo
Alzheimer Disease
Potency
Animals
Aspartic Acid Endopeptidases
Humans
Pharmacology (medical)
Enzyme Inhibitors
education
Cells, Cultured
Neurons
education.field_of_study
Amyloid beta-Peptides
Organic Chemistry
Brain
In vitro
Mice, Inbred C57BL
Molecular Medicine
Female
Amyloid Precursor Protein Secretases
Biotechnology
Subjects
Details
- ISSN :
- 1573904X
- Volume :
- 31
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Pharmaceutical research
- Accession number :
- edsair.doi.dedup.....31cf692d99871c71d467cbcf1453646e