Abstract 4425: Oral efficacy and preclinical ADME evaluation of CKD-516, a novel tubulin polymerization inhibitor

Abstract

Abstract CKD-516 is a potent anticancer agent that inhibits microtubule assembly and disrupts tumor vasculature (VDA). CKD-516 is an amino acid prodrug of S516 releasing S516 in vivo. Previously we reported the discovery and its antitumor efficacy of CKD-516 as well as various in vitro studies (Abstract 5561, 2009 AACR). As a continuation of the investigation, a detailed ADME evaluation of CKD-516 in both rats and dogs and its potential as an oral agent is described in this report. Following intravenous administration to rats and dogs, CKD-516 rapidly became the active metabolite S516 in plasma and the half-lives of S516 were 1.5 hrs in rats, and 8 hrs in dogs. Protein binding was high with an unbound fraction less than or equal to 20% in all species tested. In distribution studies in rats dosed intravenously, S516 was mainly distributed in thymus, lung and stomach and had a short half-life less than 2 hrs in all tissues tested. In rats, the excretion of CKD-516 in urine, bile and feces amounted to 0.22%, 8.22% and 4.92%, respectively. S516 was found to have comparable metabolic stabilities both in dog and human liver microsomes where there was no difference between male and female microsomes. However, the rate of metabolism in rats from male and female liver microsomes were markedly different. In general, S516 is expected to have low drug-drug interaction with IC50 values of >10 μM against most CYP450 enzymes but had a moderate inhibition against CYP450 1A2 and 2C8. The intestinal absorption of CKD-516 was predicted to be moderate to high as the apparent permeabilities (×106 cm/sec) of CKD-516 and its active metabolite S516 in Caco-2 permeability assay were 15.1 and 35.4, respectively. Thus, CKD-516 was found to have an acceptable oral bioavailability in rats, supporting its potential efficacy as an oral agent. In vivo antitumor experiments were performed in the HCT116 human tumor xenograft model. When the established tumor reached the size of 150 mm3, CKD-516 was administered to mice orally. Groups of animals were received CKD-516 with doses of 10 mg/kg or 20 mg/kg (Q4d × 5). The treated group showed a tumor growth suppression (IR = 50∼60%). Drug related toxicity and body weight decrease were not detected at doses tested. In summary, a complete ADME characterization of CKD-516, a novel tubulin polymerization inhibitor and VDA, both in vitro and in vivo was described. Moreover, CKD-516 was found to have a good potential as an oral agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4425.