We have completed a single ascending dose clinical study of the proposed chemopreventive agent 3, 3’-dindolylmethane (DIM). The study agent was nutritional-grade, absorption-enhanced 3, 3’-diindolylmethane (BR-DIM™),a product of BioResponse, LLC (Boulder, CO). We have completed our examination of the safety and tolerability of single doses of BR-DIM in drug-free, non-smoking, healthy men and women, and have determined the single-dose pharmacokinetics of BR-DIM in these subjects. Groups of four subjects were enrolled for each dose level. After randomization, one subject in each group received placebo while the other three received BR-DIM. Doses administered to groups were 50, 100, 150, 200, and 300 mg DIM, with the 300 mg dose repeated in an additional group of four subjects. No adverse effects were reported at doses up to 150 mg. At the 200 mg dose, one subject reported nausea and vomiting, but after breaking code was found to have received placebo. At the 300 mg dose, one of six subjects receiving BR-DIM reported mild nausea and headache and one reported nausea and vomiting. Only the latter effect was judged as probably related to study agent. Analysis of serial plasma samples showed that only one subject at the 50 mg dose had detectable concentrations of DIM. The single 100 mg DIM dose from BR-DIM resulted in a mean Cmax of 32 ng/ml, and a mean AUC of 136 ng*hr/ml, and a single 200 mg dose produced a mean Cmax of 104 ng/ml and a mean AUC of 417 ng*hr/ml. The single 300 mg DIM dose from BR-DIM resulted in a mean Cmax of 108 ng/ml and a mean AUC of 532 h*ng/ml. We conclude that BR-DIM is well tolerated at single doses of up to 200 mg DIM, and that increasing the dose to 300 mg DIM did not result in a proportional increase in Cmax, and elicited only a non-dose-proportional increase in AUC. These findings have been used in the design of a multiple daily dose study which is currently in progress. Supported by NCI Contract N01-CN-35008.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA