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 a humanized 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.