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Xenobiotica
the fate of foreign compounds in biological systems
Volume 49, 2019 - Issue 12
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General Xenobiochemistry

Prediction of human pharmacokinetics of long half-life compounds using chimeric mice with humanised liver

, , , , , & show all
Pages 1379-1387 | Received 01 Dec 2018, Accepted 03 Feb 2019, Published online: 18 Mar 2019
 

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.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Disclosure statement

No potential conflict of interest was reported by the authors.

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