Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft

Abstract

Effective treatments for primary brain tumors and brain metastases represent a major unmet medical need. Targeting the CDK4/CDK6-cyclin D1-Rb-p16/ink4a pathway using a potent CDK4 and CDK6 kinase inhibitor has potential for treating primary central nervous system tumors such as glioblastoma and some peripheral tumors with high incidence of brain metastases. We compared central nervous system exposures of two orally bioavailable CDK4 and CDK6 inhibitors: abemaciclib, which is currently in advanced clinical development, and palbociclib (IBRANCE; Pfizer), which was recently approved by the U.S. Food and Drug Administration. Abemaciclib antitumor activity was assessed in subcutaneous and orthotopic glioma models alone and in combination with standard of care temozolomide (TMZ). Both inhibitors were substrates for xenobiotic efflux transporters P-glycoprotein and breast cancer resistant protein expressed at the blood-brain barrier. Brain K p,uu values were less than 0.2 after an equimolar intravenous dose indicative of active efflux but were approximately 10-fold greater for abemaciclib than palbociclib. K p,uu increased 2.8-and 21-fold, respectively, when similarly dosed in P-gp-deficient mice. Abemaciclib had brain area under the curve (0-24 hours) K p,uu values of 0.03 in mice and 0.11 in rats after a 30 mg/kg p.o. dose. Orally dosed abemaciclib significantly increased survival in a rat orthotopic U87MG xenograft model compared with vehicle-treated animals, and efficacy coincided with a dose-dependent increase in unbound plasma and brain exposures in excess of the CDK4 and CDK6 K i values. Abemaciclib increased survival time of intracranial U87MG tumor-bearing rats similar to TMZ, and the combination of abemaciclib and TMZ was additive or greater than additive. These data show that abemaciclib crosses the blood-brain barrier and confirm that both CDK4 and CDK6 inhibitors reach unbound brain levels in rodents that are expected to produce enzyme inhibition; however, abemaciclib brain levels are reached more efficiently at presumably lower doses than palbociclib and are potentially on target for a longer period of time.

Efflux Transporters at the Blood-Brain Barrier Limit Delivery and Efficacy of Cyclin-Dependent Kinase 4/6 Inhibitor Palbociclib (PD-0332991) in an Orthotopic Brain Tumor Model

“…The largest increase in brain exposure was observed in the Mdr1a/b 2/2 Bcrp1 2/2 mice, with an ∼115-fold increase in brain distribution, again showing that both transporters are critical in limiting delivery. Consistent with recent reports (de Gooijer et al, 2015;Raub et al, 2015), we have shown that the efflux transporters P-gp and BCRP play a significant role in the brain delivery of palbociclib. Furthermore, our data in the current study indicate that the limited brain delivery of palbociclib may be the reason behind the lack of efficacy of palbociclib in the orthotopic GBM22 model.…”

Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer

“…Finally, because preclinical data have shown that abemaciclib crosses the blood-brain barrier and prolongs survival in intracranial human brain tumor xenografts [24], paired cerebrospinal fluid (CSF) and unbound plasma concentrations of abemaciclib were obtained from 10 patients with glioblastoma in the JPBA trial [21]. The results showed that abemaciclib concentrations detected in the CSF approximate those in plasma.…”

Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors

“…Tumor growth inhibition is observed in multiple other human cancer xenograft models, including those derived from non-small cell lung cancer (NSCLC), melanoma, glioblastoma, and mantle cell lymphoma (21)(22)(23). Abemaciclib distributes across the blood-brain barrier and prolongs survival in an intracranial glioblastoma xenograft model ( 24 ), suggesting potential effi cacy against primary and metastatic tumors involving the central nervous system.…”