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

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 (t_1/2) in humans. In this study, the predictability of t_1/2 in humans using PXB mice®, chimeric mice with humanised liver, was assessed using 14 compounds showing long t_1/2 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 (CL_t) and distribution volume (Vd_ss) were predicted from single-species scaling. Using the obtained parameters, the t_1/2 in humans was predicted. Using PXB mice, the predicted t_1/2 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 t_1/2 in humans.