Abstract 3371: Preclinical disposition and pharmacokinetics of volitinib, a novel selective cMet inhibitor .

Volitinib is a novel selective cMet inhibitor. This study is to evaluate its preclinical ADME/PK profile. Volitinib has high membrane permeability (Papp (A>B) 28×10 − 6 cm/s) without efflux transport across Caco-2 cell monolayer and exhibits negligible P-gp inhibition (IC 50 > 17 μM). Metabolic stability of volitinib in liver microsomes and S9 fractions of rat, dog, monkey and human was evaluated. Five phase I metabolites were observed in liver microsomes and S9 fractions of different species, and three major metabolites resulted from demethylation (M1), hydroxylation (M2) and mono-oxygenation (M3) were found to be mediated by multiple enzymes, including CYP450s and aldehyde oxidase. Rat was the most similar species to human in terms of the in vitro metabolism and metabolite profile. Metabolism is the main route of elimination for volitinib in rat due to the fact that the fecal, urinary and biliary excretion of the parent volitinib accounted for max max =1.9 h) and moderately low distribution (Vss=0.7 L/kg), the poor oral bioavailability (1.9%) of volitinib in monkey is considered to be the result of excessive first-pass extraction. Overall, volitinib exhibited favorable preclinical PK/ADME properties. Citation Format: Yi Gu, Yang Sai, Jian Wang, Sumei Xia, Guanglin Wang, Yuansheng Zhao, Li Zhang, Wenqing Yang, Guangxiu Dai, Weihan Zhang, Qisun Gong, Zhenping Tian, Weiguo Su. Preclinical disposition and pharmacokinetics of volitinib, a novel selective cMet inhibitor . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3371. doi:10.1158/1538-7445.AM2013-3371