Phase 1 Multiple-Dose Safety, Pharmacokinetic, and Drug Interaction Clinical Study of Nutritional-Grade, Absorption-Enhanced DIM (BR-DIM)
18 Years
70 Years
Both
Unspecified Adult Solid Tumor, Protocol Specific
Trial Information
Phase 1 Multiple-Dose Safety, Pharmacokinetic, and Drug Interaction Clinical Study of Nutritional-Grade, Absorption-Enhanced DIM (BR-DIM)
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.
Inclusion 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
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention
Outcome Measure:
Effect of diindolylmethane (BR-DIM) on activities of CYP3A4 and CYP1A2
Outcome Description:
Descriptive statistics will be calculated on all variables of interest: frequencies and percentages will be used to summarize categorical variables and medians, and ranges will summarize quantitative variables. Paired t-tests will be used to compare enzyme levels post-pre at each dose. Analysis of covariance will be used to determine if there is a dose effect on enzyme levels, using the baseline values as a covariate. If there is no dose effect, the seven subjects at each dose will be pooled which will provide an increase power to detect meaningful changes in enzyme levels.
Outcome Time Frame:
Up to 1 week
Safety Issue:
No
Principal Investigator
Reed Greg
Investigator Role:
Principal Investigator
Investigator Affiliation:
University of Kansas
Authority:
United States: Food and Drug Administration
Study ID:
NCI-2009-00867
NCT ID:
NCT00392652
Start Date:
November 2006
Completion Date:
Related Keywords:
- Unspecified Adult Solid Tumor, Protocol Specific
Name | Location |
|---|---|
| University of Kansas Medical Center | Kansas City, Kansas 66160-7353 |
