Pharmacokinetics of panobinostat: Inter-species difference in metabolic stability

Abstract

Panobinostat is a potent pan-HDAC inhibitor that has been tested in multiple studies for the treatment of brain tumors. There have been contrasting views surrounding its efficacy for the treatment of tumors in the CNS following systemic administration when examined in different models or species. We conducted experiments using three different mouse strains or genotypes to have a more comprehensive understanding of the systemic as well as the CNS distributional kinetics of panobinostat. Our study found that panobinostat experienced rapid degradation in vitro in FVB mouse matrices and a faster degradation rate was observed at 37{degree sign}C compared with room temperature and 4{degree sign}C, suggesting that the in vitro instability of panobinostat was due to enzymatic metabolism. Panobinostat also showed inter-strain and inter-species differences in the in vitro plasma stability; and was stable in human plasma. The objective of this study was to examine the in vitro metabolic stability of panobinostat in different matrices and assess the influence of that metabolic stability on the in vivo pharmacokinetics and CNS delivery of panobinostat. Importantly, the plasma stability in various mouse strains was not reflected in the in vivo systemic pharmacokinetic behavior of panobinostat. Several hypotheses arise from this finding, including: the binding of panobinostat to red blood cells, the existence of competing endogenous compounds to enzyme(s), the distribution into tissues with a lower level of enzymatic activity or the metabolism occurring in the plasma is a small fraction of the total metabolism in vivo Significance Statement Panobinostat showed different in vitro degradation in plasma from different mouse strains and genotypes. However, despite the differences surrounding in vitro plasma stability, panobinostat showed similar in vivo pharmacokinetic behavior in different mouse models. This suggests that the inter-strain difference in enzymatic activity did not affect the in vivo pharmacokinetic behavior of panobinostat and its CNS distribution in mice. This lack of translation between in vitro metabolism assays and in vivo disposition can confound drug development.

Keywords: ABC efflux transporters; CNS pharmacokinetics; blood-brain barrier; distribution; drug metabolism.