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，在人类中安全使用的历史很长。DIM已在多种前列腺癌和其他癌症的转化模型中显示出化学预防和化学治疗活性，并已在临床上进行评估（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、结晶的DIM在水中极低的溶解度限制了目前制剂中DIM的口服生物利用度。一种新的DIM制剂（BR-9001）已经被开发出来，它有望显著提高DIM的口服生物利用度和良好的耐受性。本任务单的目的是在临床前评估这种新制剂。在任务1中，我们打算确定这种新配方DIM在大鼠体内的药代动力学（PK）。旧的提法BR-DIM也应作为比较指标列入同一研究。PK和毒性桥接研究应在任务2中启动。本研究将在给药28天后对新制剂在大鼠体内的PK和毒理学进行评价。基于先前在大鼠和人类中获得的相对相似的DIM浓度，给予相似剂量的DIM（以每体表面积毫克为基础），大鼠是本研究的合适物种。此外，为了支持临床试验，至少需要28天的给药时间，因为DIM的全身浓度似乎随着每日给药而下降（狗在给药12周后，人在给药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).