DHB Supplement Interaction Study
Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Healthy Volunteers
Phase: N/A
Status: Recruiting
Sponsored by: National Institute of Environmental Health Sciences (NIEHS) Official(s) and/or principal investigator(s): Shepherd H Schurman, M.D., Principal Investigator, Affiliation: National Institute of Environmental Health Sciences (NIEHS)
Overall contact: Aparna Purushotham, Ph.D., Phone: (919) 541-9839, Email: aparna.purushotham@nih.gov
Summary
Background:
- Drinking grapefruit juice changes how long it takes some medicines to be broken down in
the body. Researchers have found that a substance in grapefruit juice called DHB
contributes to this effect. Some dietary supplements contain DHB and claim to increase
the absorption of any and all supplements, medicine or any other drug. But these usually
contain a lot more DHB than a glass of grapefruit juice. Researchers want to study the
effects of grapefruit juice and supplements with DHB.
Objective:
- To compare how a certain dietary supplement (sold as DHB-300 ) versus grapefruit
juice affects how long it takes a person s body to break down medicines.
Eligibility:
- Healthy volunteers ages 18 - 60.
Design:
- Participants will be screened with medical history, physical exam, and blood and urine
tests.
- Participants will have 3 treatment visits. Participants cannot drive themselves home
from the visits. Each visit lasts about 13. 5 hours and includes:
- Questions about medications and participant s health.
- Vital signs taken.
- A finger probe to measure oxygen.
- Blood and urine sampling throughout the visit.
- An IV line inserted into an arm vein. It will stay there throughout the visit.
- Study treatments:
- Midazolam hydrochloride a syrup given to make people sleepy.
- Loperamide a tablet for treating diarrhea.
- 1 glass of water, 1 glass of grapefruit juice, or 1 pill of DHB-300. A different one
will be given at each treatment visit.
- One week before each visit, participants cannot have certain fruits and juices. They
must fast the night before each visit.
- For the 3 days after each visit, participants will return to the clinic 4 times. Their
vital signs will be checked and blood will be drawn.
Clinical Details
Official title: A Pharmacokinetic Study to Assess the Drug Interaction Risk of the Grapefruit Juice Component and Dietary Supplement 6',7'-Dihydroxybergamottin
Study design: Time Perspective: Prospective
Primary outcome: Pharmacokinetic measures (AUC0 inf, Cmax) of systemic drug exposure
Secondary outcome: Geometric means, estimates of treatment differences, within-subject and between-subject treatment variance, and the 95% confidence intervals around those estimates
Detailed description:
The grapefruit juice component 6 ,7 - dihydroxybergamottin (DHB) is an irreversible
inhibitor of intestinal cytochrome P450 3A (CYP3A). A single serving (240 mL) of grapefruit
juice (GFJ) contains less than or equal to 5 mg of DHB. The pharmacokinetic boosting
effect of GFJ has fueled the marketing of DHB-containing dietary supplements that enhance
absorption naturally, with product labels ranging from 50 to 300 mg of DHB. The effect
of such DHB-containing dietary supplements on the pharmacokinetics of CYP3A-metabolized
drugs is unknown. This single-center, open-label, randomized, 3-period, single-dose,
crossover study in healthy volunteers will compare the drug interaction risk of a
DHB-containing dietary supplement (DHB-300[ ]) with GFJ. The primary objective of this
study is to compare the effects of a DHB supplement with those of GFJ and water on the
pharmacokinetics of two model substrates, the FDA-recommended CYP3A probe substrate
midazolam, and the dual CYP3A/P-glycoprotein (P-gp) substrate loperamide. This dual-probe
substrate approach to assess drug interaction risk will provide mechanistic insight into any
interaction observed. Eligible volunteers (n=12) will undergo 3 phases, each comprising an
exposure visit and 4 subsequent post-exposure visits to collect blood and urine over 72 or
12 hours, respectively. Exposure visits will be scheduled at least 2 weeks apart to allow
washout between the phases. At each exposure visit, participants will be administered oral
doses of midazolam hydrochloride (2. 5 mg) and loperamide (16 mg) concomitantly with water
(240 mL), GFJ (240 mL), or DHB-300[ ] (with 240 mL water) according to a randomized
treatment sequence. Blood and urine will be collected pre-dose and post-dose over 72
(blood) or 12 (urine) hours for subsequent analyses of relevant pharmacokinetic outcomes of
each probe substrate, including the primary endpoints area under the concentration-time
curve from time zero (pre-dose) to infinity (AUC0-inf) and maximum observed concentration
(Cmax). Secondary endpoints include geometric means, estimates of treatment differences,
within-subject and between-subject treatment variance, as well as the 95% confidence
intervals around those estimates.
Eligibility
Minimum age: 18 Years.
Maximum age: 60 Years.
Gender(s): Both.
Criteria:
- INCLUSION CRITERIA:
Age 18-60
Men and non-pregnant women
Participant in the Environmental Polymorphisms Registry. Prior to enrollment in this study
the participant will be required to enroll in the Environmental Polymorphisms Registry.
Willing to abstain from fruit juices, star fruit, grapefruit and grapefruit-related fruits
(e. g., pomelo, Seville orange), and grapefruitcontaining products for 1 week prior to
Exposure Visits and for the 4 follow-up visits.
Willing to fast (with the exception of water) from midnight prior to the screening visit
and each Exposure Visit, including abstaining from
alcohol and caffeinated beverages
Ability to successfully complete treatment visits, including securing transportation
EXCLUSION CRITERIA:
Women who are currently pregnant or breastfeeding
Current use of known CYP3A inhibitors or inducers, which in the opinion of the
Investigator poses an unacceptable risk to the patient or to the validity of study
results. Candidates will be asked about medication use during the screening process and on
the day of the exposure visits. The collected data will be reviewed by the PI or designee
to confirm the candidates eligibility.
Known liver dysfunction or disease as defined by:
- ALT - higher than the normative value and/or determined abnormal by the PI
- AST higher than the normative value and/or determined abnormal by the PI
- ALP higher than the normative value and/or determined abnormal by the PI
Known kidney dysfunction or disease or:
- Estimated Glomerular Filtration Rate (eGFR)- < 60 ml/min per the MDRD equation
Heart disease
Pre-existing and known history of psychiatric disorders
Known history of Myasthenia gravis
Current use of quinidine, ritonavir, and saquinavir (potential interaction with
loperamide)
Current use of study drug-related medications (benzodiazepines, opioids, herbal
supplements; temporary discontinuation per the investigator s discretion may be
allowed). Candidates will be asked about medication use during the screening process and
also during each of their exposure visits. The collected data will be reviewed by the PI
or designee to confirm the candidates eligibility.
Known allergy or hypersensitivity to any study treatments (i. e., to GFJ, DHB, midazolam,
loperamide), any opioids, or benzodiazepines
History of acute-angle glaucoma
History of sleep apnea
Current diagnosis of anemia, as defined by hemoglobin concentration < 13 g/dL for males
and hemoglobin concentration < 11 g/dL for females or hematocrit values (determined by
lancet-induced drop of blood from the fingertip or via clinical labs) of < 56% for both
sexes.
Blood donation within the past 8 weeks
Use of medications for which consumption of GFJ is contraindicated and which in the
opinion of the Investigator would pose an unacceptable risk to the patient if discontinued
or continued while consuming GFJ. Candidates will be asked about medication use during the
screening process. The collected data will be reviewed by the PI or designee to confirm
the candidates eligibility.
Any other conditions or substance use that in the opinion of the Investigator would pose
an unacceptable risk to the patient or to the validity of the study results. Candidates
will be asked about health conditions during the screening process. The collected data
will be reviewed by the PI or designee to confirm the candidates eligibility.
BMI > 35.
Locations and Contacts
Aparna Purushotham, Ph.D., Phone: (919) 541-9839, Email: aparna.purushotham@nih.gov
NIEHS Clinical Research Unit (CRU), Research Triangle Park, North Carolina, United States; Recruiting
Additional Information
NIH Clinical Center Detailed Web Page
Related publications: de Castro WV, Mertens-Talcott S, Derendorf H, Butterweck V. Grapefruit juice-drug interactions: Grapefruit juice and its components inhibit P-glycoprotein (ABCB1) mediated transport of talinolol in Caco-2 cells. J Pharm Sci. 2007 Oct;96(10):2808-17. Paine MF, Oberlies NH. Clinical relevance of the small intestine as an organ of drug elimination: drug-fruit juice interactions. Expert Opin Drug Metab Toxicol. 2007 Feb;3(1):67-80. Review. Lang M, Seifert MH, Wolf KK, Aschenbrenner A, Baumgartner R, Wieber T, Trentinaglia V, Blisse M, Tajima N, Yamashita T, Vitt D, Noda H. Discovery and hit-to-lead optimization of novel allosteric glucokinase activators. Bioorg Med Chem Lett. 2011 Sep 15;21(18):5417-22. doi: 10.1016/j.bmcl.2011.06.128. Epub 2011 Jul 18.
Starting date: September 2014
Last updated: August 7, 2015
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