Panobinostat penetrates the blood-brain barrier and achieves effective brain concentrations in a murine model.

Abstract

Panobinostat, an orally bioavailable pan-HDAC inhibitor, has demonstrated potent activity in multiple malignancies, including pediatric brain tumors such as DIPG, with increased activity against H3K27M mutant cell lines. Given limited evidence regarding the CNS penetration of panobinostat, we sought to characterize its BBB penetration in a murine model. Panobinostat 15mg/kg was administered IV to 12 CD-1 female mice. At specified time points, mice were euthanized, blood samples were collected, and brains were removed. LC-MS was performed to quantify panobinostat concentrations. Cmax and AUC were estimated and correlated with previously published pharmacokinetic analyses and reports of IC-50 values in DIPG cell lines. Mean panobinostat plasma concentrations (ng/mL) were 27.3 ± 2.5 at 1h, 7.56 ± 1.8 at 2h, 1.48 ± 0.56 at 4h, and 2.33 ± 1.18 at 7h. Mean panobinostat brain concentrations (ng/g) were 60.5 ± 6.1 at 1h, 42.9 ± 5.4 at 2h, 33.2 ± 6.1 at 4h, and 28.1 ± 4.3 at 7h. Brain-to-plasma ratio at 1h was 2.22 and the brain to plasma AUC ratio was 2.63. Based on the published human pharmacokinetic data, the anticipated Cmax in humans is expected to be significantly higher than the IC-50 identified in DIPG models. It is expected that panobinostat would be effective in CNS tumors where the IC-50 is in the low nanomolar range. Thus, our data demonstrate panobinostat crosses the BBB and achieves concentrations above the IC-50 for DIPG and other brain tumors and should be explored further for clinical efficacy.