Characterizing the pharmacokinetics of panobinostat in a non-human primate model for the treatment of diffuse intrinsic pontine glioma.

Abstract

Diffuse intrinsic pontine glioma (DIPG) is one of the deadliest forms of childhood cancers. To date, no effective treatment options have been developed. Recent drug screening studies identified the HDAC inhibitor panobinostat as an active agent against DIPG cells lines and animal models. To guide in the clinical development of panobinostat, we evaluated the CNS pharmacokinetics of panobinostat using CSF as a surrogate to CNS tissue penetration in a pre-clinical nonhuman primate (NHP) model after oral administration. Panobinostat was administered orally to NHP (n = 3) at doses 1.0, 1.8, 2.4, and 3.0mg/kg (human equivalent dose: 20, 36, 48, 60mg/m2, respectively). The subjects served as their own controls where possible. Serial, paired CSF and plasma samples were collected for 0-48h. Panobinostat was quantified via a validated uHPLC-MS/MS method. Pharmacokinetic (PK) parameters were calculated using non-compartmental methods. CSF penetration of panobinostat after systemic delivery was low, with levels detectable in only two subjects. The CSF penetration of panobinostat was low following oral administration in this pre-clinical NHP model predictive of human PK.