Preclinical pharmacokinetic and pharmacodynamic evaluation of novel anticancer agents, ON01910.Na (Rigosertib, Estybon™) and ON013105, for brain tumor chemotherapy

Silpa Nuthalapati, Qingyu Zhou, Ping Guo, Hua Lv, Stephen Cosenza, M. V.Ramana Reddy, E. Premkumar Reddy, James M. Gallo

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Purpose To evaluate a mitotic inhibitor, ON01910.Na, as a potential chemotherapeutic agent for brain tumors using a series of PK/ PD studies, which led to the evaluation of its structural analog, ON013105, a prodrug of the more lipophilic product,ON013100. Methods Systemic PK characterization of ON01910 and ON013105 was completed in healthy mice. Using an orthotopic U87 glioma mouse model, brain and brain tumor distribution under steady-state conditions were evaluated for ON01910.Na and ON013105/ON013100; anticancer potential following a multiple-dose schedule of 250 mg/kg/day IP for 7 days was evaluated for ON01910.Na. Results ON01910 exhibited low brain and brain tumor distribution with quasi-steady-state brain/plasma (Cssbrain/Cssplasma) and brain tumor/plasma (Cssbrain tumor/Cssplasma) concentration ratios of 0.03 ±0.02 and 0.14±0.08, respectively. Significant antiangiogenic potential and antiproliferative capacity of ON01910 in the intracerebral model was absent. ON013100 showed high brain and brain tumor penetration with Cssbrain/Cssplasma and Css brain tumor/Cssplasma ratios of 0.92±0.26 and 1.35±0.40, respectively; its prodrug ON013105 showed negligible brain and brain tumor penetration. Conclusions ON013105, notON01910.Na,was identified as a potential anticancer drug candidate for further investigation in brain tumor chemotherapy based on the properties of ON013100.

Original languageEnglish
Pages (from-to)2499-2511
Number of pages13
JournalPharmaceutical Research
Volume29
Issue number9
DOIs
StatePublished - Sep 2012

Keywords

  • Brain tumor disposition
  • Glioma
  • Intracerebral
  • ON013105
  • ON01910.Na

Fingerprint

Dive into the research topics of 'Preclinical pharmacokinetic and pharmacodynamic evaluation of novel anticancer agents, ON01910.Na (Rigosertib, Estybon™) and ON013105, for brain tumor chemotherapy'. Together they form a unique fingerprint.

Cite this