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Xenobiotica. 2017 Dec;47(12):1052-1063. doi: 10.1080/00498254.2016.1265160. Epub 2017 Mar 2.

Comparison of predictability for human pharmacokinetics parameters among monkeys, rats, and chimeric mice with humanised liver.

Author information

1
a Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , Fujisawa , Japan.

Abstract

1. The aim of the present study was to evaluate the usefulness of chimeric mice with humanised liver (PXB mice) for the prediction of clearance (CLt) and volume of distribution at steady state (Vdss), in comparison with monkeys, which have been reported as a reliable model for human pharmacokinetics (PK) prediction, and with rats, as a conventional PK model. 2. CLt and Vdss values in PXB mice, monkeys and rats were determined following intravenous administration of 30 compounds known to be mainly eliminated in humans via the hepatic metabolism by various drug-metabolising enzymes. Using single-species allometric scaling, human CLt and Vdss values were predicted from the three animal models. 3. Predicted CLt values from PXB mice exhibited the highest predictability: 25 for PXB mice, 21 for monkeys and 14 for rats were predicted within a three-fold range of actual values among 30 compounds. For predicted human Vdss values, the number of compounds falling within a three-fold range was 23 for PXB mice, 24 for monkeys, and 16 for rats among 29 compounds. PXB mice indicated a higher predictability for CLt and Vdss values than the other animal models. 4. These results demonstrate the utility of PXB mice in predicting human PK parameters.

KEYWORDS:

Chimeric humanised mouse; PXB mouse; clearance (CL); prediction; single-species allometric scaling (SSS); volume of distribution (Vd)

PMID:
27892765
DOI:
10.1080/00498254.2016.1265160
[Indexed for MEDLINE]

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