Permeability, binding and distributional kinetics of Ponatinib, a multi-kinase inhibitor: implications for the treatment of brain tumors

Abstract

Glioblastoma (GBM) is the most common malignant brain tumor and one of the unmet medical needs. Among over 1,000 GBM clinical trials testing molecularly-targeted agents, no single agent has demonstrated drastic improvement in patient survival, in part due to manifold drug delivery challenges to the brain tumor. Advances in genomic and proteomic technologies have identified numerous oncogenic targets, such as mutated or amplified receptor tyrosine kinase pathways, which have enabled proteomic-guided drug selection for the treatment of GBM. Despite these advances, drug discovery and development for the treatment of GBM is still complexed by the challenges that are unique to the brain tumor that resides behind the blood-brain barrier (BBB), a formidable barrier for reaching therapeutic drug concentration in the brain tumor. Many molecularly-targeted drugs that have been examined for the treatment of GBM are a substrate of two highly expressed BBB efflux transporters, P-glycoprotein (P-gp) and Breast cancer resistance protein (Bcrp). This dissertation examined the multiple drug delivery challenges, including central nervous system (CNS) penetration, binding, and distributional kinetics and the implications on drug efficacy and/or toxicity, for a tyrosine kinase inhibitor (ponatinib) that can serve as a case example.