Prediction of human pharmacokinetics of long half-life compounds using chimeric mice with humanised liver.
Xenobiotica
; 49(12): 1379-1387, 2019 Dec.
Article
em En
| MEDLINE
| ID: mdl-30744481
ABSTRACT
1. The prediction of human pharmacokinetic (PK) parameters is an important theme to select drug candidates from preclinical studies. It is essential to improve the prediction accuracy of compound half-life (t1/2) in humans. In this study, the predictability of t1/2 in humans using PXB mice®, chimeric mice with humanised liver, was assessed using 14 compounds showing long t1/2 in humans. 2. After intravenous administration of the compounds to PXB mice, the plasma concentration-time profiles were fitted using one- or two-compartment models and the human clearance (CLt) and distribution volume (Vdss) were predicted from single-species scaling. Using the obtained parameters, the t1/2 in humans was predicted. Using PXB mice, the predicted t1/2 values of 71.4% of the compounds were within two-fold of the actual values. Meanwhile, based on predictions using SCID mice, the host strain of the PXB mice, only 7.1% of tested compounds were within two-fold. 3. In conclusion, we demonstrated the novel utility of PXB mice for human PK predictions of compounds having long t1/2 in humans.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Farmacocinética
/
Fígado
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Xenobiotica
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Japão