Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.)
Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.).
J Pharmacol Exp Ther. 2023 Dec;387(3):315-327. doi: 10.1124/jpet.123.001826. Epub 2023 Oct 12.
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-histone deacetylase inhibitor that is being tested in preclinical and clinical studies, including for the treatment of pediatric medulloblastoma, which has a propensity for leptomeningeal spread and diffuse midline glioma, 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 P-glycoprotein (P-gp) and breast cancer resistant protein (Bcrp), which are major efflux transporters expressed at the BBB. The CNS delivery of panobinostat was moderately limited by P-gp and Bcrp, and the unbound tissue-to-plasma partition coefficient 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 STATEMENT: This study shows that the central nervous system (CNS) penetration of panobinostat is limited by P-gp and Bcrp, and its efficacy may be limited by inadequate distribution to the tumor. 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 preclinical and clinical trial study design and may guide treatment for these devastating brain tumors in children.
实现治疗药物在靶部位的充分暴露是化疗有效的关键决定因素。考虑到这一点，开发中枢神经系统（CNS）肿瘤治疗方法的主要挑战是克服递药障碍，包括血脑屏障（BBB）。帕比司他是一种非选择性的组蛋白去乙酰化酶抑制剂，目前正在进行临床前和临床试验，包括治疗小儿髓母细胞瘤，该肿瘤有向软脑膜扩散的倾向，弥漫性中线胶质瘤可浸润至幕上脑区。在这项研究中，我们研究了帕比司他在小鼠中枢神经系统中的分布速率、程度和空间异质性。转运蛋白缺陷型小鼠研究表明，帕比司他是 P-糖蛋白（P-gp）和乳腺癌耐药蛋白（Bcrp）的双重底物，这两种蛋白都是 BBB 上表达的主要外排转运蛋白。P-gp 和 Bcrp 对帕比司他的中枢神经系统传递有一定的限制，在野生型小鼠的脑和脊髓中，帕比司他的未结合组织-血浆分配系数分别为 0.32 和 0.21。此外，静脉给药后，帕比司他在脑内各区域分布不均，表明其疗效可能受到肿瘤位置或软脑膜扩散的存在和程度的影响。使用房室 BBB 模型进行模拟提示，按照推荐的口服剂量方案，患者体内的自由帕比司他在大脑中的暴露量不足。因此，可能需要采用替代方法将药物递送至中枢神经系统，以确保自由帕比司他充分暴露，从而治疗广泛的小儿脑肿瘤。意义：本研究表明，帕比司他的中枢神经系统渗透受到 P-gp 和 Bcrp 的限制，其疗效可能受到分布至肿瘤部位不足的限制。帕比司他在不同脑区的分布不均匀，表明其疗效可能取决于肿瘤的解剖位置。这些小鼠中枢神经系统的分布参数可为临床前和临床试验的研究设计提供信息，并可能为儿童这些毁灭性脑肿瘤的治疗提供指导。
