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Xenobiotica
the fate of foreign compounds in biological systems
Volume 49, 2019 - Issue 4
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General Xenobiochemistry

Prediction of human pharmacokinetics of typical compounds by a physiologically based method using chimeric mice with humanized liver

, , , , ORCID Icon &
Pages 404-414 | Received 31 Jan 2018, Accepted 29 Mar 2018, Published online: 19 Apr 2018
 

Abstract

  1. In this study, total body clearance (CLt), volume of distribution at steady state (Vss) and plasma concentration–time profiles in humans of model compounds were predicted using chimeric mice with humanized livers.

  2. On the basis of assumption that unbound intrinsic clearance (CLUint) per liver weight in chimeric mice was equal to those in humans, CLt were predicted by substituting human liver blood flow and liver weights in well-stirred model. Vss were predicted by Rodgers equation using scaling factors of tissue-plasma concentration ratios (SFKp) in chimeric mice estimated from a difference between the observed and predicted Vss. These physiological approaches showed high prediction accuracy for CLt and Vss values in humans.

  3. We compared the predictability of CLt and Vss determined by the physiologically based predictive approach using chimeric mice with those from predictive methods reported by Pharmaceutical Research Manufacturers of America. The physiological approach using chimeric mice indicated the best prediction accuracy in each predictive method.

  4. Simulation of human plasma concentration–time profiles were generally successful with physiologically based pharmacokinetic (PBPK) model incorporating CLUint and SFKp obtained from chimeric mice.

  5. Combined application of chimeric mice and PBPK modeling is effective for prediction of human PK in various compounds.

Acknowledgements

The authors thank members of Phoenix Bio Co., Ltd., Hiroshima, Japan, for animal experiments.

Disclosure statement

No potential conflict of interest was reported by the authors.

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