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Sulforaphane as an Antagonist to Human PXR-mediated Drug-drug Interactions

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ClinicalTrials.gov Identifier: NCT00621309
Recruitment Status : Completed
First Posted : February 22, 2008
Results First Posted : September 6, 2019
Last Update Posted : September 6, 2019
Sponsor:
Collaborators:
Fred Hutchinson Cancer Research Center
National Institute of General Medical Sciences (NIGMS)
Information provided by (Responsible Party):
David Eaton, University of Washington

Tracking Information
First Submitted Date  ICMJE February 12, 2008
First Posted Date  ICMJE February 22, 2008
Results First Submitted Date  ICMJE November 21, 2016
Results First Posted Date  ICMJE September 6, 2019
Last Update Posted Date September 6, 2019
Study Start Date  ICMJE March 2008
Actual Primary Completion Date June 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 21, 2008)
Midazolam Clearance (Pharmacokinetic Measure of Cytochrome P450 3A4 Activity) [ Time Frame: 7 days ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Sulforaphane as an Antagonist to Human PXR-mediated Drug-drug Interactions
Official Title  ICMJE Phase I Clinical Trial to Evaluate the Efficacy of Sulforaphane as an Antagonist to Human PXR-mediated Drug-drug Interactions
Brief Summary

Adverse drug-drug interactions (DDIs) are responsible for approximately 3% of all hospitalizations in the US, perhaps costing more than $1.3 billion per year. One of the most common causes of DDIs is the when one drug alters the metabolism of another. A key enzyme in the liver and intestine, called "cytochrome P450 3A4 (CYP3A4) is generally considered to be the most important drug metabolizing enzyme. The gene for CYP3A4 can be 'turned on' by the presence of certain other drugs, resulting in much higher levels of CYP3A4 in the liver and intestine. Thus, when a drug that induces CYP3A4 is given with or before another drug that is metabolized by 3A4, a 'drug-drug' interaction occurs because the first drug (the inducer) greatly changes the rate at which the second drug (CYP3A4 substrate) is removed from the body. Many drugs increase CYP3A4 activity by binding to a receptor called the Pregnane-X-Receptor (PXR), which is a major switch that controls the expression of the CYP3A4 gene. Using human liver cells we have demonstrated that sulforaphane (SFN), found in broccoli, can block drugs from activating the PXR receptor, thereby inhibiting the switch that causes CYP3A4 induction. The purpose of this project is to determine if SFN can be used to block adverse DDIs that occur when drugs bind to and activate the PXR receptor and subsequently induce CYP3A4 activity. We will recruit 24 human volunteers to participate in the study. This project will determine whether SFN can prevent the drug Rifampin from binding to PXR and increasing CYP3A4 activity in humans following oral administration of SFN (broccoli sprout extract). The rate of removal of a small dose of the drug midazolam will be used to determine the enzymatic activity of CYP3A4 before and following treatment with Rifampin, in the presence or absence of SFN, since midazolam is only eliminated from the bloodstream by CYP3A4. . We predict that SFN will prevent the increase in midazolam clearance (metabolism) that normally follows treatment with the antibiotic, rifampicin.

This research is important because it could potentially lead to a simple, cost-effective way of preventing one of the most common causes of adverse drug-drug interactions that occurs today. For example, rifampicin, which is a cheap and effective antibiotic used to treat TB, cannot be used in HIV/AIDS patients because it increases the metabolism of many of the antiretroviral drugs used to treat HIV/AIDS. TB is a major opportunistic infection in AIDS patients, so this is a serious clinical problem, especially in developing countries where more expensive alternative drug therapies are not available. We hypothesize that co-formulation of rifampicin with SFN could block this drug-drug interaction without altering its efficacy, thereby allowing its use in HIV/AIDS patients infected with TB. This is but one example of numerous drug-drug interactions that occur via this mechanism.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Adverse Drug Interactions
Intervention  ICMJE
  • Drug: Rifampicin
    Rifampicin, an antibiotic used to treat TB, is administered at a dose of 300 mg day x 7 days to induce CYP3A5.
    Other Names:
    • Rifampin
    • rifamycin
    • Rimactane
    • Rifadin
  • Dietary Supplement: sulforaphane plus rifampicin
    Sulforaphane (SFN) is an isothiocyanate derived from the plant phytochemical, glucoraphinin. It appears to inhibit ligand binding to the ligand activated nuclear transcription factor, Pregnane X-Receptor (PXR). This arm tests the hypothesis that SFN can block ligand binding to the PXR, thereby inhibiting transcriptional activation of PXR-regulated genes. Sulforaphane is administered daily for 7 days as a broccoli sprout extract, at a dose rate of 75 mg (~420 umoles)per day for 7 days. Rifampicin is also administered once per day at a dose rate of 300 mg/day for 7 days.
    Other Names:
    • sulforaphane: glucoraphinin (precursor); 1-Isothiocyanato-4-methylsulfinyl-butane
    • Rifampicin: Rifampin, Rifadin, Rimactane
  • Dietary Supplement: sulforaphane alone
    Sulforaphane (SFN) is an isothiocyanate derived from the plant phytochemical, glucoraraphinin. It appears to inhibit ligand binding to the ligand activated nuclear transcription factor, Pregnane X-Receptor (PXR). This arm tests the hypothesis that SFN can block ligand binding to the PXR, thereby inhibiting transcriptional activation of PXR-regulated genes
    Other Name: 1-isothiocyanato-4-(methylsulphinyl)butane
Study Arms  ICMJE
  • Active Comparator: 1
    Subjects are given 300 mg / 7 days of rifampicin to induce CYP3A4. Midazolam clearance is measured on the 8th day.
    Intervention: Drug: Rifampicin
  • Active Comparator: 2
    Sulforaphane (SFN), a natural product derived from broccoli sprouts, is utilized as a putative inhibitor of ligand (Rifampin) activation of the Pregnane X-receptor. In this arm, both SFN (putative inhibitor of ligand binding to PXR) and Rifampin (strong activating ligand of PXR) are given together.
    Intervention: Dietary Supplement: sulforaphane plus rifampicin
  • Active Comparator: 3
    This arm involves the administration of Sulforaphane (SFN) alone, in the absence of the PXR ligand, rifampicin. The hypothesis is that SFN will have no effect on the expression of PXR-regulated genes. Alternatively, it is possible that SFN could inhibit as yet unidentified endogenous ligands to the PXR receptor, thereby causing down-regulations of genes regulated wholely or in part by PXR. SFN is administered as a broccoli sprout extract at a dose rate of 75 mg (~420 umoles) per day for 7 days.
    Intervention: Dietary Supplement: sulforaphane alone
Publications * Poulton EJ, Levy L, Lampe JW, Shen DD, Tracy J, Shuhart MC, Thummel KE, Eaton DL. Sulforaphane is not an effective antagonist of the human pregnane X-receptor in vivo. Toxicol Appl Pharmacol. 2013 Jan 1;266(1):122-31. doi: 10.1016/j.taap.2012.10.029. Epub 2012 Nov 12.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 15, 2019)
29
Original Estimated Enrollment  ICMJE
 (submitted: February 21, 2008)
24
Actual Study Completion Date  ICMJE September 2010
Actual Primary Completion Date June 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Adults from all ethnicities will be encouraged to participate, with our recruitment efforts we expect similar profile as that of the greater Seattle area.

Exclusion Criteria:

Exclusion criteria address a mix of medical and practical issues and include:

  • Medical history of gastrointestinal, hepatic, or renal disorders
  • Pregnancy or lactation
  • Known allergies/intolerances to any foods used in the feeding trial
  • Weight loss or gain greater than 4.5 kg within the past year
  • Major changes in eating habits within the past year (e.g. adoption of a faddish diet)
  • Antibiotic use within the past 3 months
  • Body weight greater than 150% of desirable
  • Exercise patterns that require or result in major changes in diet
  • Current use of prescription medication (including oral contraceptives)
  • Current use of over-the-counter medications and herbal supplements
  • Regular exposure to passive smoke
  • Occupational exposure to smoke or organic solvents
  • Food dislikes that would preclude participation in the feeding trial
  • Alcohol intake of greater than 2 drinks/day (2 drinks=720 mL beer, 240 mL wine, or 9 mL spirits). Additionally, before the trial, participants will have a blood draw to be sent to the UW Medical Center Lab for liver and kidney functions profile and pregnancy test for women. Those with abnormal test results will be excluded as well as pregnant women.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 40 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00621309
Other Study ID Numbers  ICMJE 33109
NIH grant: 1R01GM079280-01A1;
07-9114-A01
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party David Eaton, University of Washington
Study Sponsor  ICMJE University of Washington
Collaborators  ICMJE
  • Fred Hutchinson Cancer Research Center
  • National Institute of General Medical Sciences (NIGMS)
Investigators  ICMJE
Principal Investigator: David L Eaton, PhD University of Washington
PRS Account University of Washington
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP