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

Autor:	Zhang W; 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.) elmqu011@umn.edu zhan4937@umn.edu., Oh JH; 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.)., Zhang W; 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.)., Rathi 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.)., Larson JD; 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.)., Wechsler-Reya RJ; 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.)., Sirianni RW; 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.)., Elmquist WF; 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.) elmqu011@umn.edu zhan4937@umn.edu.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2023 Dec; Vol. 387 (3), pp. 315-327. Date of Electronic Publication: 2023 Oct 12.
DOI:	10.1124/jpet.123.001826
Abstrakt:	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. (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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