The extrapolation of drug exposure between species remains a frightening part of drug development, adding towards the low rate of success of drug approval. As a result, extrapolation of toxicology from animal models to humans to judge safe, first-in-human (FIH) doses requires high safety margins. We hypothesized that the human-CYP3A4-expressing transgenic (Cyp3aXAV) mouse is really a more predictive model for human drug exposure of CYP3A4-metabolized small-molecule drugs. Population pharmacokinetic models according to wild-type (WT) and Cyp3aXAV mouse pharmacokinetic data of dental lorlatinib, brigatinib, ribociclib and fisogatinib were allometrically scaled and when compared with human exposure. Extrapolation from the Cyp3aXAV mouse model carefully predicted the observed human exposure for lorlatinib and brigatinib having a 1.1-fold and 1.-fold difference, correspondingly, over a 2.1-fold and 1.9-fold deviation for WT-based extrapolations of lorlatinib and brigatinib, correspondingly. For ribociclib, the extrapolated WT mouse model gave better predictions having a 1.-fold deviation over a .3-fold deviation for that extrapolated Cyp3aXAV mouse model. Because of the insufficient an individual population pharmacokinetic model for fisogatinib, only median maximum concentration ratios were calculated, leading to ratios of 1. and .6 for WT and Cyp3aXABLU-554V rodents extrapolations, correspondingly. The greater accurate predictions of human exposure in preclinical research in line with the Cyp3aXAV mouse model can ultimately lead to FIH doses connected with improved safety and effectiveness as well as in greater success in drug development.