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).
