Population PKPD modeling of BACE1 inhibitor-induced reduction in Aß levels in vivo and correlation to in vitro potency in primary cortical neurons from mouse and guinea pig.
Pharm Res
; 31(3): 670-83, 2014 Mar.
Article
en En
| MEDLINE
| ID: mdl-24092053
ABSTRACT
PURPOSE:
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 ß (Aß) in brain and cerebrospinal fluid, and to establish the correlation between in vitro and in vivo potency of novel ß-secretase (BACE1) inhibitors.METHODS:
BACE1-mediated inhibition of Aß 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 Aß production rate was used to estimate unbound in vivo IC 50 in a population pharmacokinetic-pharmacodynamic modeling approach.RESULTS:
Estimated in vivo inhibitory potencies varied between 1 and 1,000 nM. The turnover half-life of Aß40 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.CONCLUSION:
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Péptidos beta-Amiloides
/
Ácido Aspártico Endopeptidasas
/
Inhibidores Enzimáticos
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Secretasas de la Proteína Precursora del Amiloide
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Enfermedad de Alzheimer
/
Neuronas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
/
Male
Idioma:
En
Revista:
Pharm Res
Año:
2014
Tipo del documento:
Article