Clinical trial NCT00392652: Diindolylmethane in Healthy Volunteers
Official title: Phase 1 Multiple-Dose Safety, Pharmacokinetic, and Drug Interaction Clinical Study of Nutritional-Grade, Absorption-Enhanced DIM (BR-DIM)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy, no Evidence of Disease
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-10-26
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This randomized phase I trial is studying the side effects and best dose of diindolylmethane in healthy volunteers. Chemoprevention is the use of certain drugs or substances to keep cancer from forming, growing, or coming back. The use of diindolylmethane may keep cancer from forming. Collecting and storing samples of blood and urine from healthy volunteers to study in the laboratory may help doctors learn more about the way a person's body handles the drug.

Detailed description: PRIMARY OBJECTIVES:

I. Determine the effect of multiple daily dosing with nutritional-grade, absorption-enhanced diindolylmethane (BR-DIM) on the disposition of probe drugs metabolized by cytochrome P4501A2 (CYP1A2) and CYP3A4 in healthy volunteers.

SECONDARY OBJECTIVES:

I. Determine the effect of multiple daily doses of BR-DIM on estrogen metabolites in urine and on activities of CYP2C9, CYP2D6, and P-glycoprotein/OATP.

II. Determine the effect of a single dose of BR-DIM on the disposition of probe drugs that are metabolized or transported by CYP1A2, CYP2C9, CYP2D6, CYP3A4, and P-glycoprotein (P-go).

III. Determine the safety and tolerability of single and multiple daily doses of BR-DIM.

IV. Determine the pharmacokinetics of a single dose of BR-DIM and of the same dose after chronic daily dosing.

V. Determine the pharmacokinetics of a single dose of BR-DIM and of the same dose after chronic daily dosing.

TERTIARY OBJECTIVES:

I. To determine effects of BR-DIM on activities of glutathione-S-transferase (GST), a phase 2 enzyme, in lymphocytes.

OUTLINE: This is a randomized, double-blind study. Participants are stratified according to gender. Participants are randomized to 1 of 2 intervention arms.

Arm I: Participants receive low-dose oral diindolylmethane (BR-DIM) twice daily for 4 weeks.

Arm II: Participants receive high-dose oral BR-DIM twice daily for 4 weeks.

In both arms, participants receive an oral probe-drug cocktail comprising caffeine (CYP1A2), dextromethorphan (CYP2D6), buspirone (CYP3A4), losartan (CYP2C9), and fexofenadine (P-glycoprotein) before randomization and after the first and last dose of BR-DIM.

Blood and urine are collected periodically for pharmacokinetic profiles of BR-DIM and probe drugs.

After completion of study intervention, participants are followed at 1 week.

Eligibility criteria: Criteria:

* Healthy men and women
* Nonsmoker confirmed by urine cotinine test
* No active malignancy
* Life expectancy \>= 12 months
* Hemoglobin \> 10 g/dL
* Absolute granulocyte count \> 1,500/mm\^3
* Creatinine \< 2.0 mg/dL
* Albumin \> 3.0 g/dL
* Bilirubin \< 1.8 mg/dL
* AST and ALT \< 110 U/L
* Alkaline phosphatase \< 300 U/L
* Body mass index =\< 30
* Not pregnant or nursing
* Negative pregnancy test
* Fertile participants must use effective nonhormonal contraception
* No acute, unstable, chronic, or recurring medical conditions
* No strict vegetarians or consumption of \> 3 medium servings (1/2 cup each) of cruciferous vegetables per week
* Participants who have stopped eating cruciferous vegetables within the past 2 weeks and agree to refrain from eating them for the duration of the study are eligible
* Cruciferous vegetables include broccoli, cabbage (including coleslaw), cauliflower, bok-choy, brussels sprouts, collards, kale, kohlrabi, mustard greens, rutabaga, turnip, and watercress
* No serious drug allergies or other serious intolerance or allergies
* Mild seasonal allergies allowed
* No chronic conditions, including headaches, dysphoria, fatigue, dizziness, blurred vision, insomnia, rhinorrhea, nausea, vomiting, abdominal pain, diarrhea, constipation, menopausal hot flashes/night sweats, or clinically significant premenstrual syndrome
* No serious acute or chronic illness
* No requirement for chronic drug therapy
* No alcohol ingestion within 48 hours of study treatment
* No investigational drugs within the past 3 months
* No prior chemotherapy
* No concurrent regular medications or hormones
* No recent change in medications or dosage of medications
* No concurrent regular supplements or vitamins
* No concurrent over-the-counter medications
* No concurrent grapefruit or its juice

Primary outcomes:
measure: Effect of diindolylmethane (BR-DIM) on activities of CYP3A4 and CYP1A2
timeFrame: Up to 1 week
measure: Grade 2 or higher toxicities, graded using NCI CTC version 2.0
timeFrame: Up to 1 week
measure: Steady-state pharmacokinetic parameters such as half-life, Cmax, Tmax, and AUC
timeFrame: Up to 1 week
Secondary outcomes:
measure: Drug metabolizing enzyme values (CYP2C9, CYP2D6, P-glycoprotein/OATP, and glutathione-S-transferase)
timeFrame: Up to 1 week
measure: 2/16 alpha OHE ratio in urine
timeFrame: Up to 1 month
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
Study officials:
affiliation: University of Kansas Medical Center
name: Reed Greg
role: PRINCIPAL_INVESTIGATOR
References: