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

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 (Css(brain)/Css(plasma)) and brain tumor/plasma (Css(brain tumor)/Css(plasma)) 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 Css(brain)/Css(plasma) and Css(brain tumor)/Css(plasma) ratios of 0.92 ± 0.26 and 1.35 ± 0.40, respectively; its prodrug ON013105 showed negligible brain and brain tumor penetration.

CONCLUSIONS:

ON013105, not ON01910.Na, was identified as a potential anticancer drug candidate for further investigation in brain tumor chemotherapy based on the properties of ON013100.

• Authors: Silpa Nuthalapati, Qingyu Zhou, Ping Guo, Hua Lv, Stephen Cosenza, M V Ramana Reddy, E Premkumar Reddy, James M Gallo
• Journal: Pharmaceutical research (Pharm Res) Vol. 29 Issue 9 Pg. 2499-511 (Sep 2012) ISSN: 1573-904X [Electronic] United States
• PMID: 22678771 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology, therapeutic use)
• Brain Neoplasms (drug therapy)
• Chromatography, Liquid
• Drug Evaluation, Preclinical
• Mice
• Tandem Mass Spectrometry