Preclinical comparison of the blood brain barrier (BBB) permeability of osimertinib with other EGFR TKIs

Preclinical comparison of the blood brain barrier (BBB) permeability of osimertinib with other EGFR TKIs:

Purpose Osimertinib is a potent and selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing and T790M resistance mutations. To treat metastatic brain disease, blood brain barrier (BBB) permeability is considered desirable for increasing clinical efficacy. Experimental Design We examined the level of brain penetration for 16 irreversible and reversible EGFR-TKIs using multiple in-vitro and in-vivo BBB preclinical models. Results In-vitro osimertinib was the weakest substrate for human BBB efflux transporters (efflux ratio 3.2). In-vivo rat free brain to free plasma ratios (Kpuu) show osimertinib has the most BBB penetrance (0.21), compared to the other TKIs (Kpuu ≤ 0.12). PET imaging in cynomolgus macaques demonstrated osimertinib was the only TKI amongst those tested to achieve significant brain penetrance (Cmax %ID 1.5, brain/blood Kp 2.6). Desorption electrospray ionisation mass spectroscopy (DESI-MS) images of brains from mouse PC9 macro-metastases models showed osimertinib readily distributes across both healthy brain and tumor tissue. Comparison of osimertinib to the poorly BBB penetrant afatanib in a mouse PC9 model of subclinical brain metastases showed only osimertinib has a significant effect on rate of brain tumor growth. Conclusion These preclinical studies indicate that osimertinib can achieve significant exposure in the brain compared with the other EGFR-TKIs tested and supports the ongoing clinical evaluation of osimertinib for the treatment of EGFRm brain metastasis. This work also demonstrates the link between low in-vitro transporter efflux ratios and increased brain penetrance in-vivo supporting the use of in-vitro transporter assays as an early screen in drug discovery.