IGF::OT::IGF HHSN2612015000241 PERIOD OF PERFORMANCE: 9/15/16 TO 10/14/2018 PRECLINICAL EVALUATION OF A NEW LIPID-BASED SMEDDS

二吲哚基甲烷（DIM）是吲哚-3-甲醇的主要体内衍生物，存在于十字花科蔬菜中，据报道具有抗炎、抗增殖和免疫调节特性，在人类中具有广泛的安全使用历史。DIM已在前列腺和其他癌症的多种转化模型中显示出化学预防和化学治疗活性，并已进行临床评估（前列腺上皮内瘤变（PIN）和宫颈上皮内瘤变（CIN）临床试验）。然而，纯的结晶DIM在水中的极低溶解度限制了DIM在当前制剂中的口服生物利用度。 已经开发了一种新的DIM制剂（BR-9001），预计其可显著提高DIM的口服生物利用度和良好的耐受性。本任务订单的目的是对这种新制剂进行临床前评价。在任务1中，我们打算确定DIM新制剂在大鼠中的药代动力学（PK）。旧制剂BR-DIM也应作为对照药物纳入同一研究。 应在任务2中启动PK和毒性桥接研究。本研究将评价BR-9001给药28天后新制剂在大鼠中的PK和毒理学。 基于先前在给予相似剂量DIM（以mg/体表面积计）的大鼠和人体中达到的相对相似的DIM浓度，大鼠是本研究的适当种属。此外，需要至少28天的给药以支持临床试验，因为DIM的全身浓度似乎随着每日给药而下降（犬给药12周后，人给药4周后）。

Diindolylmethane (DIM) is the major in vivo derivative of indole-3-carbinol, which is present in cruciferous vegetables and has been reported to possess anti-inflammatory, anti-proliferative, and immune-modulating properties with an extensive history of safe use in humans. DIM has demonstrated chemopreventive and chemotherapeutic activity in multiple translational models of prostate and other cancers, and has been evaluated clinically (Prostatic Intraepithelial Neoplasia (PIN) and Cervical Intraepithelial Neoplasia (CIN) clinical trials). However, the extremely low solubility of pure, crystalline DIM in water limits the oral bioavailability of DIM in current formulations. A new formulation of DIM (BR-9001) has been developed which is expected to yield significantly greater oral bioavailability and good tolerability of DIM. The purpose of this task order is to evaluate this new formulation pre-clinically. In Task 1, we intend to determine the pharmacokinetics (PK) of this new formulation of DIM in rats. The older formulation, BR-DIM, shall also be included in the same study as a comparator. A PK and toxicity bridging study shall be initiated in Task 2. This study shall evaluate the PK and toxicology of the new formulation in rats after 28 days of BR-9001 administration. Based on the relatively similar DIM concentrations achieved previously in rats and humans administered similar doses of DIM (on a mg per body surface area basis), the rat is an appropriate species for this study. In addition, dosing of at least 28 days shall be required to support a clinical trial, as systemic concentrations of DIM appear to decline with daily dosing (dogs after 12 weeks of dosing, and humans after 4 weeks of dosing).