Abstract 3371: Preclinical disposition and pharmacokinetics of volitinib, a novel selective cMet inhibitor .
Authors: Gu Yi , Sai Yang , Wang Jian , Xia Sumei , Wang Guanglin , Zhao Yuansheng , Zhang Li , Yang Wenqing , Dai Guangxiu , Zhang Weihan , Gong Qisun , Tian Zhenping , Su Weiguo 
Published: August 2014

Volitinib is a novel selective cMet inhibitor. This study is to evaluate its preclinical ADME/PK profile. Volitinib has high membrane permeability (Papp (A&gt;B) 28×10−6 cm/s) without efflux transport across Caco-2 cell monolayer and exhibits negligible P-gp inhibition (IC50 &gt; 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 &lt;2% of the dose. The total of 16 phase I metabolites and 8 phase II metabolites were identified in plasma and excreta of rat. M22, a sulfate conjugate of a monooxidized metabolite M5, dominated with the abundance in all tested matrices. Demethylation to M2 excreted in urine was also an important elimination pathway in rat. Volitinib showed no significant reversible or mechanism-based CYP inhibition in human liver microsomes, and no induction of CYP1A2 and CYP3A4 in human hepatocytes. Volitinib had moderate plasma protein binding rate (60%∼70% in rat, dog, and human; 40% in mouse; 80% in monkey) and exhibited wide distribution to different organs in rat, with high exposures in liver and kidney, very low in brain, spinal cord and testis comparing to the plasma level. In PK studies in mouse, rat and dog, Volitinib showed the rapid oral absorption (Tmax&lt;2.5 h) with high exposures and the acceptable bioavailability at 27.2%, 42.6% and 86.3%, respectively. The in vivo clearance (CL) was 11.0, 11.8 and 3.5 mL/min/kg in mouse, rat and dog, respectively, revealing a low extraction ratio. The volume of distribution in steady state (Vss) was 0.4, 1.4 and 1.4 L/kg in those species, respectively, indicating a moderate to low distribution pattern. Volitinib also displayed linear pharmacokinetics (PK) in the dose ranges of 1 to 25 mg/kg in rat and 2 to 10 mg/kg in dog. Food hardly affected its PK profile in dog. In contrast, volitinib in monkey showed a notably high extraction ratio (CL=17.2 mL/min/kg) consistent with the in vitro metabolism result. Considering the rapid absorption of volitinib (Tmax=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