Preclinical Development – Chemical
2019 PharmSci 360
The ability of anticancer drugs to penetrate and remain in the brain is of considerable clinical relevance because many tumors metastasise to this location. Entrectinib is a potent TRKA/B/C, ROS1 and ALK inhibitor, in clinical development for treating tumors with NTRK/ROS1 gene fusions. Entrectinib was found to be a P-gp substrate in vitro, with a high efflux ratio (ER) observed in a conventional P-gp assay. However, entrectinib showed high steady-state brain/plasma concentration ratios in vivo, as well as demonstrating antitumor efficacy in both preclinical and clinical studies across different tumor types, including brain tumors. This proposal presents evidence for a novel ’Apical ER model‘ and in-vivo brain distribution models to demonstrate unequivocally that entrectinib is a poor P-gp substrate with greater brain penetration than other molecules in this class (crizotinib and larotrectinib), which are strong P-gp substrates. Our findings have broad implications for the preclinical characterization of new molecular entities.