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

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 (CL_t) and volume of distribution at steady state (Vd_ss), 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. CL_t and Vd_ss 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 CL_t and Vd_ss values were predicted from the three animal models.

3. Predicted CL_t 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 Vd_ss 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 CL_t and Vd_ss values than the other animal models.

4. These results demonstrate the utility of PXB mice in predicting human PK parameters.

Keywords:

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

Acknowledgements

The authors would like to thank Noriyasu Sano and Atsutoshi Furuta in Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited for their assistance with the animal experiments.

Declaration of interest

The authors have no conflicts of interest to declare.