Abstract B013: In vitro stability and in vivo pharmacokinetic behavior of panobinostat in mouse models for the treatment of CNS tumors

Abstract

Abstract Aberrant alterations of histone deacetylases (HDACs), an epigenetic regulator, are common in central nervous system (CNS) tumors and HDAC inhibitors have been found to have therapeutic potential for the treatment of CNS tumors. Panobinostat is a pan-HDAC inhibitor that has shown potency against multiple CNS tumors. Panobinostat has a hydroxamic acid side chain, a structural element reported to be susceptible to esterase activity in multiple compounds. Therefore, in vitro stability of panobinostat may allow the prediction of in vivo pharmacokinetic behavior. The objective of this study is to discover the mechanisms influencing the in vitro stability of panobinostat in multiple matrices and evaluate the in vivo pharmacokinetics in mouse models. In vitro stability studies in mouse plasma at different temperatures showed that panobinostat was unstable in mouse plasma and the decomposition rate was temperature-dependent. Meanwhile, panobinostat was stable in phosphate-buffered saline (PBS, pH7.4) tested at the same incubation conditions. Therefore, we propose that enzymatic activity is a contributor of the in vitro instability of panobinostat. Panobinonstat stability was also measured in plasma from different species. Data show that panobinostat was stable in human, monkey and dog plasma while unstable in mouse and rat plasma. The species difference observed was in line with the carboxylesterase 1c (Ces1c) expression among these species, where rodent plasma has abundant Ces1c expression while the other species have no Ces1c in plasma. With this in mind, we evaluated the impact of Ces1c removal from the matrices. We found that panobinostat was stable in plasma collected from Ces1c knockout mice (B6.Cg-Ces1ctm1.1Loc/J), indicating that Ces1c is contributing to the in vitro instability of panobinostat in plasma. To evaluate the influence of Ces1c on its pharmacokinetic behaviors, we studied the plasma and CNS distribution of panobinostat in wild-type C57BL6/J mice and Ces1c knockout mice following an intravenous bolus dose of 10 mg/kg via tail vein. Despite improved in vitro stability of panobinostat in plasma from Ces1c knockout mice compared with that in plasma from wild-type C57BL6/J, in vivo plasma concentration-time profiles were superimposable between these two genotypes. In addition, the CNS delivery of panobinostat was not influenced by the lack of Ces1c. Studies are ongoing to find potential in vivo mechanisms that are protecting the compound from robust in vitro degradation in the plasma. Citation Format: Wenqiu Zhang, Ju-Hee Oh, Wenjuan Zhang, Rachael W. Sirianni, William F. Elmquist. In vitro stability and in vivo pharmacokinetic behavior of panobinostat in mouse models for the treatment of CNS tumors [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B013.