Assessment of chimeric mice with humanized livers in new drug development: generation of pharmacokinetics, metabolism and toxicity data for selecting the final candidate compound

Abstract

1. Chimeric mice with humanized livers are expected to be a novel tool for new drug development. This review discusses four applications where these animals can be used efficiently to collect supportive data for selecting the best compound in the final stage of drug discovery.

2. The first application is selection of the final compound based on estimated pharmacokinetic parameters in humans. Since chimeric mouse livers are highly repopulated with human hepatocytes, hepatic clearance values in vivo could be used preferentially to estimate pharmacokinetic profiles for humans.

3. The second is prediction of human-specific or disproportionate metabolites. Chimeric mice reproduce human-specific metabolites of drugs under development to conform to ICH guidance M3(R2), except for compounds that were extensively eliminated by co-existing mouse hepatocytes.

4. The third is identifying metabolites with distinct pharmacokinetic profiles in humans. Slow metabolite elimination specifically in humans increases its exposure level, but if its elimination is faster in laboratory animals, the animal exposure level might not satisfy ICH guidance M3(R2).

5. Finally, two examples of reproducing acute liver toxicity in chimeric mice are introduced. Integrated pharmacokinetics, metabolism and toxicity information are expected to assist pharmaceutical scientists in selecting the best candidate compound in new drug development.

• Chimeric mouse
• humanized liver
• liver toxicity
• metabolism prediction
• MIST guidance
• pharmacokinetics

Acknowledgements

We thank Dr. C. Tateno of PhoenixBio Co., Ltd., Dr. H. Suemizu of the Central Institute for Experimental Animals and Professor H. Yamazaki of Showa Pharmaceutical University for their encouragement and valuable advice for preparing this manuscript. We also acknowledge Drs. D. Buckley and D. Oien of XenoTech, LLC, Lenexa, KS for correcting the English manuscript.