Food-drug Interaction
Conditions
Brief summary
Purpose: Grapefruit juice is one of the most extensively studied dietary/natural substances shown to interact with a variety of medications. However, unanswered questions remain regarding the causative ingredients and mechanisms underlying such drug-grapefruit juice interactions. Compounds in grapefruit juice called furanocoumarins have been established as major causative ingredients, which act by inhibiting the elimination (metabolism) of drugs, leading to increased circulating drug concentrations. Increased drug concentrations can in turn lead to increased drug potency or even toxicity. Grapefruit juice also has been shown, paradoxically, to decrease circulating concentrations of some drugs, including the non-sedating antihistamine agent, fexofenadine (Allegra), which undergoes negligible metabolism. Whether or not furanocoumarins mediate the decrease in fexofenadine concentrations is unknown. The purpose of the proposed study is to compare the effects of a furanocoumarin-free grapefruit juice with grapefruit juice on circulating concentrations of fexofenadine.
Detailed description
Participants: Healthy volunteers of any race/ethnicity, ranging in age from 18 to 65 years, will be enrolled. Procedures (methods): Procedures will include administration of water, furanocoumarin-free grapefruit juice, or grapefruit juice with fexofenadine; placement of an intravenous (IV) line; and collection of blood over 72 hours.
Interventions
DRUGFexofenadine
This randomized, open-label, single-dose, 3-way crossover study in healthy volunteers will be conducted in the CTRC. Once subjects are identified as eligible to participate, based on their screening evaluation and according to inclusion/exclusion criteria, they will undergo 3 phases. By randomized crossover design, the subject will receive fexofenadine with water, grapefruit juice, or furanocoumarin-free grapefruit juice.
Sponsors
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Men or women between the ages of 18 and 65 * Normal screening laboratory test results * Able to understand the informed consent form * Willing to abstain from grapefruit products and all fruit juices for one week prior to and during the study * Willing to abstain from alcohol and caffeinated beverages the evening prior to each study day
Exclusion criteria
* History of intolerance to grapefruit products * History of any allergy or hypersensitivity to grapefruit products or fexofenadine * History of significant medical conditions that the study physician believes would increase risk * History of significant alcohol abuse and/or illicit drug use * Tobacco use within the month preceding the study * Pregnancy or breast-feeding * Taking concomitant medications, both prescription and non-prescription (including herbal products), known to alter fexofenadine blood levels or P-gp and/or OATP activity (women stabilized on hormonal methods of birth control will be allowed to participate)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary Pharmacokinetic Measure: Area Under the Curve (AUC) | 0-72 hours |
Countries
United States
Participant flow
Recruitment details
Screening began in September 2009. Potential eligible subjects presented for a screening visit at the UNC Clinical and Translational Research Center (CTRC) within 1 month prior to the first day of the study.
Pre-assignment details
No significant events/approaches for overall study following participant enrollment but prior to group assignment. 18 subjects recruited and screened. No exclusions.
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1: Water, GFJ, Furanocoumarin-free GFJ This randomized, open-label, single-dose, 3-way crossover study in healthy volunteers will be conducted in the CTRC. Once subjects are identified as eligible to participate, based on their screening evaluation and according to inclusion/exclusion criteria, they will undergo 3 phases. By randomized crossover design, the subject will receive fexofenadine with water, grapefruit juice (GFJ), and furanocoumarin-free grapefruit juice (depending on Williams design sequence) with at least 10 day washout in between each treatment period. | 3 |
| Sequence 2: Water, Furanocoumarin-free GFJ, GFJ This randomized, open-label, single-dose, 3-way crossover study in healthy volunteers will be conducted in the CTRC. Once subjects are identified as eligible to participate, based on their screening evaluation and according to inclusion/exclusion criteria, they will undergo 3 phases. By randomized crossover design, the subject will receive fexofenadine with water, grapefruit juice (GFJ), and furanocoumarin-free grapefruit juice (depending on Williams design sequence) with at least 10 day washout in between each treatment period. | 3 |
| Sequence 3: GFJ, Furanocoumarin-free GFJ, Water This randomized, open-label, single-dose, 3-way crossover study in healthy volunteers will be conducted in the CTRC. Once subjects are identified as eligible to participate, based on their screening evaluation and according to inclusion/exclusion criteria, they will undergo 3 phases. By randomized crossover design, the subject will receive fexofenadine with water, grapefruit juice (GFJ), and furanocoumarin-free grapefruit juice (depending on Williams design sequence) with at least 10 day washout in between each treatment period. | 3 |
| Sequence 4: GFJ, Water, Furanocoumarin-free GFJ This randomized, open-label, single-dose, 3-way crossover study in healthy volunteers will be conducted in the CTRC. Once subjects are identified as eligible to participate, based on their screening evaluation and according to inclusion/exclusion criteria, they will undergo 3 phases. By randomized crossover design, the subject will receive fexofenadine with water, grapefruit juice (GFJ), and furanocoumarin-free grapefruit juice (depending on Williams design sequence) with at least 10 day washout in between each treatment period. | 3 |
| Sequence 5: Furanocoumarin-free GFJ, GFJ, Water This randomized, open-label, single-dose, 3-way crossover study in healthy volunteers will be conducted in the CTRC. Once subjects are identified as eligible to participate, based on their screening evaluation and according to inclusion/exclusion criteria, they will undergo 3 phases. By randomized crossover design, the subject will receive fexofenadine with water, grapefruit juice (GFJ), and furanocoumarin-free grapefruit juice (depending on Williams design sequence) with at least 10 day washout in between each treatment period. | 3 |
| Sequence 6: Furanocoumarin-free GFJ, Water, GFJ This randomized, open-label, single-dose, 3-way crossover study in healthy volunteers will be conducted in the CTRC. Once subjects are identified as eligible to participate, based on their screening evaluation and according to inclusion/exclusion criteria, they will undergo 3 phases. By randomized crossover design, the subject will receive fexofenadine with water, grapefruit juice (GFJ), and furanocoumarin-free grapefruit juice (depending on Williams design sequence) with at least 10 day washout in between each treatment period. | 3 |
| Total | 18 |
Baseline characteristics
| Characteristic | Sequence 5: Furanocoumarin-free GFJ, GFJ, Water | Sequence 6: Furanocoumarin-free GFJ, Water, GFJ | Total | Sequence 1: Water, GFJ, Furanocoumarin-free GFJ | Sequence 2: Water, Furanocoumarin-free GFJ, GFJ | Sequence 3: GFJ, Furanocoumarin-free GFJ, Water | Sequence 4: GFJ, Water, Furanocoumarin-free GFJ |
|---|---|---|---|---|---|---|---|
| Age, Continuous Mean | 33 years STANDARD_DEVIATION 9.1 | 30 years STANDARD_DEVIATION 7.5 | 36 years STANDARD_DEVIATION 12 | 26 years STANDARD_DEVIATION 1 | 34 years STANDARD_DEVIATION 17 | 51 years STANDARD_DEVIATION 11 | 39 years STANDARD_DEVIATION 11 |
| Region of Enrollment United States | 3 participants | 3 participants | 18 participants | 3 participants | 3 participants | 3 participants | 3 participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 9 Participants | 2 Participants | 1 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 9 Participants | 1 Participants | 2 Participants | 3 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Primary Pharmacokinetic Measure: Area Under the Curve (AUC)
Time frame: 0-72 hours
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Water | Primary Pharmacokinetic Measure: Area Under the Curve (AUC) | Grapefruit juice | 3.2 micromolar*hr |
| Water | Primary Pharmacokinetic Measure: Area Under the Curve (AUC) | Water | 4.2 micromolar*hr |
| Water | Primary Pharmacokinetic Measure: Area Under the Curve (AUC) | Modified grapefruit juice | 3.1 micromolar*hr |
| Grapefruit Juice | Primary Pharmacokinetic Measure: Area Under the Curve (AUC) | Grapefruit juice | 3.2 micromolar*hr |
| Grapefruit Juice | Primary Pharmacokinetic Measure: Area Under the Curve (AUC) | Water | 4.2 micromolar*hr |
| Grapefruit Juice | Primary Pharmacokinetic Measure: Area Under the Curve (AUC) | Modified grapefruit juice | 3.1 micromolar*hr |
| Furanocoumarin-free Grapefruit Juice | Primary Pharmacokinetic Measure: Area Under the Curve (AUC) | Water | 4.2 micromolar*hr |
| Furanocoumarin-free Grapefruit Juice | Primary Pharmacokinetic Measure: Area Under the Curve (AUC) | Modified grapefruit juice | 3.1 micromolar*hr |
| Furanocoumarin-free Grapefruit Juice | Primary Pharmacokinetic Measure: Area Under the Curve (AUC) | Grapefruit juice | 3.2 micromolar*hr |
Comparison: For juice comparisons, fexofenadine + furanocoumarin-free grapefruit juice will be the test agent (numerator) and fexofenadine + grapefruit juice will be the reference standard (denominator).p-value: 0.7890% CI: [0.4, 1.5]t-test, 2 sided