Abstract 3286: Oral bioavailability, permeability, CYP profiling, identification of major metabolites, tissue distribution and excretion profile of a novel triple kinase inhibitor, JI-101 in rats

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Objectives JI-101 is a novel orally active kinase inhibitor has shown potent in vitro and in vivo anticancer activity against a variety of cancer cell lines and xenografts It is currently entering phase II clinical development for the treatment of solid tumors The aim of the study is to determine the pharmacokinetics (PK), absolute oral bioavailability, tissue distribution, protein binding, CYP profiling, major in vivo metabolites identification and mass balance of JI-101 in S D rats Experimental To determine the pharmacokinetics, tissue distribution and excretion of JI-101 experiments were conducted in S D rats Besides Caco-2 permeability, metabolic stability, CYP profiling and bile excretion studies were done to assess permeability across gastro-intestinal tract, to identify the major CYPs involved in the metabolism of JI-101 and putative metabolites prediction Subsequently the metabolites were identified by LC-MS/MS Results and discussion JI-101 was found to be stable in both preclinical and human liver microsomes CYP3A4 was the primary isozyme involved in the metabolism of JI-101 JI-101 excreted through bile along with its mono- and di-hydroxy metabolites The putative metabolites concentrations were negligible in systemic circulation JI-101 is highly permeable and not a substrate for P-gp In a parallel study design, JI-101 was administered to S D rats as a single oral and intravenous dose of 30 and 3 mg/kg, respectively Plasma samples were analyzed for the concentrations of JI-101, using a validated LC-MS/MS assay Following oral administration JI-101 was rapidly absorbed reaching peak plasma concentration (Cmax) within 2 h The mean terminal half-life (t½) of JI-101 with intravenous and oral route was found to be 2 66 ± 0 13 h and 1 75 ± 0 79 h, respectively The total body clearance (Cl) and volume of distribution (Vd) by intravenous route for JI-101 were found to be 13 0 ± 2 62 ml/min/kg and 2 11 ± 1 42 L/kg, respectively Oral bioavailability of JI-101 was 55% The outcome of the tissue distribution study results suggest that JI-101 is primarily accumulating in lung followed by small intestine, liver and kidney The primary route of elimination for JI-101 was feces and very negligible amount of JI-101 was excreted through urine Conclusions The preclinical data suggests that JI-101 exhibits ideal properties from developability point of view The good oral bioavailability and good selective distribution may provide differentiating features from other oncology compounds in this class Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3286. doi:10.1158/1538-7445.AM2011-3286