Do Furanocoumarins Mediate the Fexofenadine-grapefruit Juice Interaction?
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| N/A |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Other: Sequence 1: Water, GFJ, FC-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), or furanocoumarin (FC)-free grapefruit juice. |
Drug: Fexofenadine
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.
Other Names:
|
| Other: Sequence 2: Water, FC-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), or furanocoumarin (FC)-free grapefruit juice. |
Drug: Fexofenadine
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.
Other Names:
|
| Other: Sequence 3: GFJ, FC-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), or furanocoumarin (FC)-free grapefruit juice. |
Drug: Fexofenadine
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.
Other Names:
|
| Other: Sequence 4: GFJ, Water, FC-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), or furanocoumarin (FC)-free grapefruit juice. |
Drug: Fexofenadine
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.
Other Names:
|
| Other: Sequence 5: FC-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), or furanocoumarin (FC)-free grapefruit juice. |
Drug: Fexofenadine
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.
Other Names:
|
| Other: Sequence 6: FC-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), or furanocoumarin (FC)-free grapefruit juice. |
Drug: Fexofenadine
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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Primary Pharmacokinetic Measure: Area Under the Curve (AUC) [0-72 hours]
Eligibility Criteria
Criteria
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)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | North Carolina Clinical and Translational Research Center | Chapel Hill | North Carolina | United States | 27599 |
Sponsors and Collaborators
- University of North Carolina, Chapel Hill
Investigators
- Principal Investigator: Mary F Paine, PhD, UNC-Chapel Hill
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IRB 09-0788
Study Results
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 Detail | No significant events/approaches for overall study following participant enrollment but prior to group assignment. 18 subjects recruited and screened. No exclusions. |
| Arm/Group Title | 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 | Sequence 5: Furanocoumarin-free GFJ, GFJ, Water | Sequence 6: Furanocoumarin-free GFJ, Water, GFJ |
|---|---|---|---|---|---|---|
| Arm/Group Description | By randomized 3-way crossover design, the subject will receive single doses of fexofenadine 120 mg (2 60mg tablets) and 240 mL of water, grapefruit juice (GFJ), and furanocoumarin-free GFJ (depending on Williams design sequence), with at least 10 day washout in between each treatment period. | By randomized 3-way crossover design, the subject will receive single doses of fexofenadine 120 mg (2 60mg tablets) and 240 mL of water, grapefruit juice (GFJ), and furanocoumarin-free GFJ (depending on Williams design sequence), with at least 10 day washout in between each treatment period. | By randomized 3-way crossover design, the subject will receive single doses of fexofenadine 120 mg (2 60mg tablets) and 240 mL of water, grapefruit juice (GFJ), and furanocoumarin-free GFJ (depending on Williams design sequence), with at least 10 day washout in between each treatment period. | By randomized 3-way crossover design, the subject will receive single doses of fexofenadine 120 mg (2 60mg tablets) and 240 mL of water, grapefruit juice (GFJ), and furanocoumarin-free GFJ (depending on Williams design sequence), with at least 10 day washout in between each treatment period. | By randomized 3-way crossover design, the subject will receive single doses of fexofenadine 120 mg (2 60mg tablets) and 240 mL of water, grapefruit juice (GFJ), and furanocoumarin-free GFJ (depending on Williams design sequence), with at least 10 day washout in between each treatment period. | By randomized 3-way crossover design, the subject will receive single doses of fexofenadine 120 mg (2 60mg tablets) and 240 mL of water, grapefruit juice (GFJ), and furanocoumarin-free GFJ (depending on Williams design sequence), with at least 10 day washout in between each treatment period. |
| Period Title: Period 1 (5 Days) | ||||||
| STARTED | 3 | 3 | 3 | 3 | 3 | 3 |
| COMPLETED | 3 | 3 | 3 | 3 | 3 | 3 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
| Period Title: Period 1 (5 Days) | ||||||
| STARTED | 3 | 3 | 3 | 3 | 3 | 3 |
| COMPLETED | 3 | 3 | 3 | 3 | 3 | 3 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
| Period Title: Period 1 (5 Days) | ||||||
| STARTED | 3 | 3 | 3 | 3 | 3 | 3 |
| COMPLETED | 3 | 3 | 3 | 3 | 3 | 3 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
| Period Title: Period 1 (5 Days) | ||||||
| STARTED | 3 | 3 | 3 | 3 | 3 | 3 |
| COMPLETED | 3 | 3 | 3 | 3 | 3 | 3 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
| Period Title: Period 1 (5 Days) | ||||||
| STARTED | 3 | 3 | 3 | 3 | 3 | 3 |
| COMPLETED | 3 | 3 | 3 | 3 | 3 | 3 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | 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 | Sequence 5: Furanocoumarin-free GFJ, GFJ, Water | Sequence 6: Furanocoumarin-free GFJ, Water, GFJ | Total |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | Total of all reporting groups |
| Overall Participants | 3 | 3 | 3 | 3 | 3 | 3 | 18 |
| Age (years) [Mean (Standard Deviation) ] | |||||||
| Mean |
26
(1.0)
|
34
(17)
|
51
(11)
|
39
(11)
|
33
(9.1)
|
30
(7.5)
|
36
(12)
|
| Sex: Female, Male (Count of Participants) | |||||||
| Female |
2
66.7%
|
1
33.3%
|
0
0%
|
2
66.7%
|
1
33.3%
|
3
100%
|
9
50%
|
| Male |
1
33.3%
|
2
66.7%
|
3
100%
|
1
33.3%
|
2
66.7%
|
0
0%
|
9
50%
|
| Region of Enrollment (participants) [Number] | |||||||
| United States |
3
100%
|
3
100%
|
3
100%
|
3
100%
|
3
100%
|
3
100%
|
18
100%
|
Outcome Measures
| Title | Primary Pharmacokinetic Measure: Area Under the Curve (AUC) |
|---|---|
| Description | |
| Time Frame | 0-72 hours |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Water | Grapefruit Juice | Furanocoumarin-free Grapefruit Juice |
|---|---|---|---|
| Arm/Group Description | For juice and water comparisons, fexofenadine + grapefruit juice or fexofenadine + furanocoumarin-free grapefruit juice will be the test agent (numerator) and fexofenadine + water will be the reference standard (denominator). | For juice and water comparisons, fexofenadine + grapefruit juice or fexofenadine + furanocoumarin-free grapefruit juice will be the test agent (numerator) and fexofenadine + water will be the reference standard (denominator). | For juice and water comparisons, fexofenadine + grapefruit juice or fexofenadine + furanocoumarin-free grapefruit juice will be the test agent (numerator) and fexofenadine + water will be the reference standard (denominator). |
| Measure Participants | 18 | 18 | 18 |
| Water |
4.2
|
4.2
|
4.2
|
| Grapefruit juice |
3.2
|
3.2
|
3.2
|
| Modified grapefruit juice |
3.1
|
3.1
|
3.1
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Grapefruit Juice, Furanocoumarin-free Grapefruit Juice |
|---|---|---|
| Comments | For juice comparisons, fexofenadine + furanocoumarin-free grapefruit juice will be the test agent (numerator) and fexofenadine + grapefruit juice will be the reference standard (denominator). | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.78 |
| Comments | ||
| Method | t-test, 2 sided | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric Mean AUC Ratio (GFJ/mGFJ) |
| Estimated Value | 0.96 | |
| Confidence Interval |
(2-Sided) 90% 0.4 to 1.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | 1 year | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||||||
| Arm/Group Title | 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 | Sequence 5: Furanocoumarin-free GFJ, GFJ, Water | Sequence 6: Furanocoumarin-free GFJ, Water, GFJ | ||||||
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | ||||||
All Cause Mortality |
||||||||||||
| 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 | Sequence 5: Furanocoumarin-free GFJ, GFJ, Water | Sequence 6: Furanocoumarin-free GFJ, Water, GFJ | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | ||||||
Serious Adverse Events |
||||||||||||
| 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 | Sequence 5: Furanocoumarin-free GFJ, GFJ, Water | Sequence 6: Furanocoumarin-free GFJ, Water, GFJ | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
Other (Not Including Serious) Adverse Events |
||||||||||||
| 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 | Sequence 5: Furanocoumarin-free GFJ, GFJ, Water | Sequence 6: Furanocoumarin-free GFJ, Water, GFJ | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | ||||||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Mary F. Paine, RPh, PhD |
|---|---|
| Organization | UNC-Chapel Hill |
| Phone | 919-966-9984 |
| mpaine@unc.edu |
- IRB 09-0788