Pdtb-12. cns penetration of the cdk4/6 inhibitor ribociclib (lee011) in non-tumor bearing mice and mice bearing orthotopic pediatric brain tumors

Pediatric patients with brain tumors have limited treatment options and poor long-term survival. CDK4/6 bound with Cyclin D regulates cell proliferation by phosphorylating retinoblastoma protein (Rb) and releasing E2F, a positive regulator of the G1/S transition. Ribociclib, a CDK4/6 inhibitor is under clinical evaluation for treatment of pediatric malignancies. We evaluated its CNS penetration in two pediatric brain tumor models (diffuse intrinsic pontine glioma [DIPG] and Group 3 medulloblastoma [G3MB]) and in normal mouse brain using cerebral microdialysis. A plasma pharmacokinetic study of 100 mg/kg orally-administered ribociclib was performed in CD1 nude mice bearing orthotopic DIPGx7 xenografts (n=9) using population-based sampling scheme to determine ribociclib plasma exposure and pharmacokinetic parameters to derive a limited sampling model (LSM) for subsequent microdialysis studies. A cerebral microdialysis study of ribociclib (100 mg/kg, oral) was performed in CD1 nude mice bearing either orthotopic glioma (DIPGx7) xenografts or G3MB allografts, or in non-tumor bearing CD1 nude mice. Plasma samples at LSM derived time-points and microdialysis samples for every 1-hr interval were collected up to 7 or 24 hrs. Plasma and microdialysis samples were analyzed using a validated LC-MS/MS method. A one-compartment plasma model with two-compartment tumor model was fitted to all data using NONMEM. The ribociclib unbound area under the plasma concentration t...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: PEDIATRIC TUMORS - PRECLINICAL STUDIES (NON-IMMUNOLOGICAL) Source Type: research