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Cancer Chemotherapy and Pharmacology

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01-08-2019 | Glioma | Short Communication

CNS penetration of the CDK4/6 inhibitor ribociclib in non-tumor bearing mice and mice bearing pediatric brain tumors

Authors: Yogesh T. Patel, Abigail Davis, Suzanne J. Baker, Olivia Campagne, Clinton F. Stewart

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2019

Abstract

Purpose

Ribociclib, an orally bioavailable small-molecule CDK4/6 inhibitor is currently undergoing evaluation to treat pediatric central nervous system (CNS) tumors. However, it is crucial that it penetrates the brain and tumor. Thus, the objectives of the present study were to derive a clinically relevant mouse dosage for cerebral microdialysis studies, and to characterize ribociclib CNS penetration in non-tumor bearing mice and in mice bearing DIPGx7 (glioma) cortical allograft tumors.

Methods

A plasma pharmacokinetic study of ribociclib (100 mg/kg, orally) was performed in CD1 nude mice bearing glioma cortical allografts to obtain initial plasma pharmacokinetic parameters and to derive D-optimal plasma sampling time-points for microdialysis studies. Using a cerebral microdialysis technique, the extracellular fluid (ECF) disposition of ribociclib was evaluated after a single oral ribociclib dose (100 mg/kg) in non-tumor bearing mice and in mice bearing glioma cortical allografts. A one-compartment plasma model with absorption and ECF compartments were fit to plasma and ECF concentration–time data using a nonlinear mixed effects modeling approach (NONMEM 7.2).

Results

The mean unbound ribociclib plasma exposure (6812 ng/ml*h) was similar to that observed clinically at recommended dosages in adults. The median ribociclib ECF to plasma partition coefficient (K_p,uu) in non-tumor bearing and glioma mice was 0.10 and 0.07, respectively, and was not statistically different (t test, p = 0.19).

Conclusions

The CNS penetration observed was encouraging enough to move ribociclib forward with preclinical efficacy studies in models of pediatric brain tumors.

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Title: CNS penetration of the CDK4/6 inhibitor ribociclib in non-tumor bearing mice and mice bearing pediatric brain tumors
Authors: Yogesh T. Patel
Abigail Davis
Suzanne J. Baker
Olivia Campagne
Clinton F. Stewart
Publication date: 01-08-2019
Publisher: Springer Berlin Heidelberg
Keywords: Glioma
Glioma
Brain Tumor
Glioma
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03864-9

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Abstract

Purpose

Methods

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Conclusions

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