Central Nervous System Distribution of Panobinostat in Preclinical Models to Guide Dosing for Pediatric Brain Tumors

Abstract

Achieving adequate exposure of the free therapeutic agent at the target is a critical determinant of efficacious chemotherapy. With this in mind, a major challenge in developing therapies for central nervous system (CNS) tumors is to overcome barriers to delivery, including the blood-brain barrier (BBB). Panobinostat is a nonselective pan-HDAC inhibitor that is being tested in pre-clinical and clinical studies, including for the treatment of pediatric medulloblastoma, which has a propensity for leptomeningeal spread, and diffuse midline glioma (DMG), which can infiltrate into supratentorial brain regions. In this study, we examined the rate, extent, and spatial heterogeneity of panobinostat CNS distribution in mice. Transporter-deficient mouse studies show that panobinostat is a dual substrate of pglycoprotein (P-gp) and breast cancer resistant protein (Bcrp), that are major efflux transporters expressed at the BBB. The CNS delivery of panobinostat was moderately limited by P-gp and Bcrp and the free partition coefficient K p,uu of panobinostat was 0.32 and 0.21 in the brain and spinal cord in wild-type mice.In addition, following intravenous administration, panobinostat demonstrated heterogeneous distribution among brain regions, indicating that its efficacy would be influenced by tumor location or the presence and extent of leptomeningeal spread. Simulation using a compartmental BBB model suggests inadequate exposure of free panobinostat in the brain following a recommended oral dosing regimen in patients.Therefore, alternative approaches to CNS delivery may be necessary to have adequate exposure of free panobinostat for the treatment of a broad range of pediatric brain tumors. Significance StatementThese results show that the CNS penetration of panobinostat is limited by P-gp and Bcrp, and its efficacy may be limited by inadequate distribution to the tumor in spinal cord. Panobinostat has heterogeneous distribution into various brain regions, indicating that its efficacy might depend on the anatomical location of the tumors. These distributional parameters in the mouse CNS can inform both pre-clinical and clinical trial study design and may eventually help guide treatment for these devastating brain tumors in children.