Brain distributional kinetics of a novel MDM2 inhibitor SAR405838: Implications for use in brain tumor therapy

Minjee Kim, Janice K. Laramy, Gautham Gampa, Karen E. Parrish, Richard Brundage, Jann N. Sarkaria, William F. Elmquist

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Achieving an effective drug concentration in the brain is as important as targeting the right pathway when developing targeted agents for brain tumors. SAR405838 is a novel molecularly targeted agent that is in clinical trials for various solid tumors. Its application for tumors in the brain has not yet been examined, even though the target, the MDM2-p53 interaction, is attractive for tumors that could occur in the brain, including glioblastoma and brain metastases. In vitro and in vivo studies indicate that SAR405838 is a substrate of P-glycoprotein (P-gp). P-gp mediated active efflux at the blood-brain barrier plays a dominant role in limiting SAR405838 brain distribution. Even though the absence of P-gp significantly increases the drug exposure in the brain, the systemic exposure, including absorption and clearance processes, were unaffected by P-gp deletion. Model-based parameters of SAR405838 distribution across the blood-brain barrier indicate the CLout of the brain was approximately 40-fold greater than the CLin. The free fraction of SAR405838 in plasma and brain were found to be low, and subsequent Kpuu values were less than unity, even in P-gp/Bcrp knockout mice. These results indicate additional efflux transporters other than P-gp and Bcrp may be limiting distribution of SAR405838 to the brain. Concomitant administration of elacridar significantly increased brain exposure, also without affecting the systemic exposure. This study characterized the brain distributional kinetics of SAR405838, a novel MDM2 inhibitor, to evaluate its potential in the treatment of primary and metastatic brain tumors.

Original languageEnglish (US)
Pages (from-to)1403-1414
Number of pages12
JournalDrug Metabolism and Disposition
Volume47
Issue number12
DOIs
StatePublished - Jan 1 2019

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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