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

IGF::OT::IGF HHSN2612015000241 执行期间：2016 年 9 月 15 日至 2018 年 10 月 14 日 新型脂质基药物的临床前评估

• 批准号: 9360365
• 负责人: DAVID MCCORMICK, PH.D. DABT
• 金额: $ 26.2万
• 依托单位: IIT RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-10-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9360365
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Biological Availability; Body Surface Area; Canis familiaris; Cervical Intraepithelial Neoplasia; Chemopreventive Agent; Clinical Trials; Dose; Drug Kinetics; Formulation; Human; Immune; Indole-3-Carbinol; Lipids; Malignant Neoplasms; Modeling; Oral; Performance; Pharmacologic Substance; Property; Prostate; Prostatic Intraepithelial Neoplasias; Rattus; Recording of previous events; Reporting; Solubility; Toxic effect; Toxicology; Water; base; cruciferous vegetable; diindolylmethane; in vivo; preclinical evaluation

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).

二吲哚甲烷 (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，在人类中安全使用具有广泛的历史。 DIM 已在前列腺癌和其他癌症的多种转化模型中表现出化学预防和化疗活性，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，纯结晶 DIM 在水中的溶解度极低，限制了当前配方中 DIM 的口服生物利用度。 一种新的 DIM 配方 (BR-9001) 已经开发出来，预计将显着提高 DIM 的口服生物利用度和良好的耐受性。该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 DIM 制剂在大鼠体内的药代动力学 (PK)。旧配方 BR-DIM 也应作为比较剂纳入同一研究中。 任务 2 中应启动 PK 和毒性桥接研究。本研究应评估新制剂在大鼠服用 BR-9001 28 天后的 PK 和毒理学。 基于先前在给予相似剂量 DIM（以每体表面积 1 mg 为基础）的大鼠和人类中获得的相对相似的 DIM 浓度，大鼠是本研究的合适物种。此外，需要至少 28 天的给药时间来支持临床试验，因为 DIM 的全身浓度似乎随着每日给药而下降（狗给药 12 周后，人类给药 4 周后）。