Brain exposure of the mesenchymal-epithelial transition inhibitor savolitinib in nonhuman primates: A positron emission tomography study.

The receptor tyrosine kinase mesenchymal-epithelial transition factor inhibitor savolitinib is currently being evaluated as a treatment in non-small cell lung cancer (NSCLC) in combination with osimertinib. NSCLC patients with epidermal growth factor receptor/anaplastic lymphoma kinase mutations appear to have a high incidence (50%-60%) of brain metastasis; hence, cancer drugs that can efficiently access the brain hold a critical advantage. In this study, savolitinib blood-brain barrier penetration properties were investigated in nonhuman primates using positron emission tomography and intravenous administration of microdoses of [¹¹C]savolitinib either as a bolus or a bolus-constant infusion. Following a bolus, rapid distribution of radioactivity to the brain was observed reaching a maximum radioactivity concentration (C_max) of 0.33% of injected radioactivity. An estimated value of the concentration ratio of the total brain-to-plasma ratio (K_p) of 0.35 was derived using kinetic positron emission tomography data analysis. Intriguingly, notwithstanding the low C_max, the estimated unbound brain-to-plasma ratio using predetermined in vitro values for free fractions in brain and plasma showed a favorable brain-to-plasma partition with a K_p,uu of 0.65. This apparent contrast could be explained by the high free fraction of savolitinib in brain tissue. To further build confidence in the estimated K_p,uu, a bolus-constant infusion protocol successfully established a brain-to-plasma concentration steady-state yielding values for K_p and K_p,uu of 0.32 and 0.60, respectively, in good agreement with the bolus study. Our findings confirm blood-brain barrier penetrance and exposure of savolitinib in the nonhuman primate brain. If a similar penetrance in humans is observed, it may help to prevent and/or treat brain metastasis in NSCLC patients. SIGNIFICANCE STATEMENT: Patients with brain malignancies are challenging to treat due to the blood-brain barrier limiting the exposure of therapeutics to the central nervous system. This study demonstrates blood-brain barrier penetrance and exposure of the mesenchymal-epithelial transition inhibitor savolitinib in the nonhuman primate brain. If a similar penetrance in humans is observed, it may help to prevent and/or treat brain metastasis in non-small cell lung cancer patients.