PDTB-12. CNS PENETRATION OF THE CDK4/6 INHIBITOR RIBOCICLIB (LEE011) IN NON-TUMOR BEARING MICE AND MICE BEARING ORTHOTOPIC PEDIATRIC BRAIN TUMORS

Abstract

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 nontumor 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 time curve was similar to that which was observed at tolerable clinical doses (e.g., 600 mg). The unbound tumor to plasma partition coefficient (Kp,uu) for ribociclib was 0.12 ± 0.09, 0.16 ± 0.11, and 0.07 ± 0.07 for normal brain, G3MB, and DIPG tumors, respectively. Using our pharmacokinetic model we simulated daily oral dosing, and observed that it did not accumulate in the brain/tumor after multiple dose administration. Overall, our results show ribociclib penetrates into the CNS and tumors, and warrant further preclinical investigation in treating pediatric CNS tumors.