Determination of intestinal permeability of rigosertib (ON 01910.Na, Estybon): correlation with systemic exposure.

Abstract

OBJECTIVES:

Rigosertib (ON 01910.Na, Estybon) is a novel, anticancer agent undergoing phase 3 clinical trials for a lead indication against myelodysplastic syndromes (MDS). In this research, the permeability of rigosertib was evaluated using the in-situ perfused rat intestine (IPRI) model to support development of an oral formulation for rigosertib for treating cancer patients.

METHODS:

Experiments (n = 6 per group) were conducted using male Sprague-Dawley rats. Studies evaluated permeability across various intestinal segments and assessed the dose-linearity of absorption over the entire intestinal length. Drug concentrations in the portal and jugular vein were collected to correlate permeability parameters with presystemic and systemic exposure.

KEY FINDINGS:

Rigosertib permeability was highest in the jejunum, although parameter estimates indicated that rigosertib was a medium permeability compound. The compound displayed nonlinear absorption in the IPRI model, suggesting a saturable transport process. Transport inhibition studies using Caco-2 cells demonstrated that rigosertib was a P-glycoprotein (P-gp) substrate. Absolute bioavailability of rigosertib (10 and 20 mg/kg, 1-h infusion) in rats was estimated to be 10-15%. However, the fraction absorbed in humans predicted from IPRI data (52%) was consistent with published clinical data for rigosertib (35% oral bioavailability).

CONCLUSIONS:

The results of this research indicated that rigosertib is a promising candidate for oral delivery. Further studies are needed to evaluate the potential impact of P-gp and other intestinal transporters on the oral absorption of this promising anticancer agent.

• Authors: Michael P White, Mariana Babayeva, David R Taft, Manoj Maniar
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 65 Issue 7 Pg. 960-9 (Jul 2013) ISSN: 2042-7158 [Electronic] England
• PMID: 23738723 (Publication Type: Journal Article)
• Copyright: © 2013 Royal Pharmaceutical Society.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Sulfones
• ON 01910
• Glycine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Biological Availability
• Biological Transport
• Caco-2 Cells
• Dose-Response Relationship, Drug
• Drug Delivery Systems
• Glycine (administration & dosage, analogs & derivatives, pharmacokinetics)
• Humans
• Intestinal Absorption
• Intestinal Mucosa (metabolism)
• Male
• Permeability
• Rats
• Rats, Sprague-Dawley
• Sulfones (administration & dosage, pharmacokinetics)