Drug-Food Interaction Study of Seville Orange Juice and Colchicine

• Sponsor: Mutual Pharmaceutical Company, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00960193
• Collaborator: (none)
• Enrollment: 24
• Location: 1
• Arms: 2
• Duration (Months): 1.9
• Patients Per Site Per Month: 12.4

Study Details

Study Description

Brief Summary

Seville orange juice is an inhibitor of the intestinal cytochrome P450 (CYP) 3A4 enzyme, one of the enzymes responsible for the metabolism of colchicine. This study will evaluate the effect of multiple daily consumptions of Seville orange juice on the pharmacokinetic profile of a single 0.6 mg dose of colchicine. A secondary objective is to evaluate the safety and tolerability of this regimen in healthy volunteers. All study subjects will be monitored for adverse events throughout the study period.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Colchicine; Other: Seville Orange Juice	Phase 1

Detailed Description

Seville orange juice is an inhibitor of the intestinal cytochrome P450 (CYP) 3A4 enzyme, one of the enzymes responsible for the metabolism of colchicine. This study will evaluate the effect of multiple daily consumptions of Seville orange juice on the pharmacokinetic profile of a single 0.6 mg dose of colchicine. Twenty-four healthy, non-smoking, non-obese, non-pregnant adult volunteers between the ages of 18 and 45 will be given one dose of colchicine (1 x 0.6 mg tablet) on Day 1, after an overnight fast. Fasting will continue for 4 hours after the dose. Blood samples will be drawn from all participants before dosing and for 24 hours post-dose to adequately define the baseline pharmacokinetics of colchicine. After a 14 day washout period, starting on the morning of Day 15 and continuing through Day 17, subjects will return to the clinic for consumption of an administered 240 ml dose of Seville orange juice in the morning and evening. At 8am on Day 18 after an overnight fast, all subjects will receive a co-administered single oral dose of colchicine (1 x 0.6 mg) and Seville orange juice (1 x 240 ml). Fasting will continue for 4 hours after the dose. Blood samples will be drawn from all participants before dosing and for 24 hours post-dose to adequately define the pharmacokinetics of colchicine in the presence of Seville orange juice. Subjects will consume the final administered 240 ml dose of Seville orange juice in the evening on Day 18. A further goal of this study is to evaluate the safety and tolerability of this regimen in healthy volunteers. Subjects will be monitored throughout participation in the study for adverse reactions to the study drug and/or procedures. Seated blood pressure and pulse will be measured prior to dosing and at approximately 1, 2, and 3 hours following drug administration on Days 1 and 18 to coincide with peak plasma concentrations of colchicine. All adverse events whether elicited by query, spontaneously reported, or observed by clinic staff will be evaluated by the investigator and reported in the subject's case report form.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: A One-Directional, Open-Label Drug-Food Interaction Study to Investigate the Effects of Multiple-Daily Consumptions of Seville Orange Juice on the Single-Dose Pharmacokinetics of Colchicine in Healthy Volunteers
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: Apr 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Colchicine Alone baseline colchicine pharmacokinetics	Drug: Colchicine; A single dose of 0.6 mg colchicine administered alone in the morning on Day 1 and a single dose of 0.6 mg colchicine administered with Seville orange juice in the morning on Day 18 after an overnight fast of at least 10 hours.
Experimental: Colchicine with Seville Orange Juice colchicine pharmacokinetics in presence of Seville orange juice	Drug: Colchicine; A single dose of 0.6 mg colchicine administered alone in the morning on Day 1 and a single dose of 0.6 mg colchicine administered with Seville orange juice in the morning on Day 18 after an overnight fast of at least 10 hours.; Other: Seville Orange Juice; 240 mL of Seville orange juice administered in the morning and evening on Days 15 to 18.

Outcome Measures

Primary Outcome Measures

1. Maximum Plasma Concentration (Cmax) of Colchicine [serial pharmacokinetic blood samples drawn immediately prior to colchicine dosing on Days 1 and 18, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after colchicine dose administration.]

   The maximum or peak concentration that colchicine reaches in the plasma.

2. Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] [Serial pharmacokinetic blood samples drawn immediately prior to colchicine dosing on Days 1 and 18, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after colchicine dose administration.]

   The area under the plasma concentration versus time curve, from time 0 to the time of the last measurable colchicine concentration (t), as calculated by the linear trapezoidal rule.

3. Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] [Serial pharmacokinetic blood samples drawn immediately prior to colchicine dosing on Days 1 and 18, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after colchicine dose administration.]

   The area under the plasma concentration versus time curve from time 0 to infinity. AUC(0-∞) was calculated as the sum of AUC(0-t) plus the ratio of the last measurable colchicine plasma concentration to the elimination rate constant.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy adults 18-45 years of age

• Non-smoking and non-pregnant (post-menopausal, surgically sterile or using effective contraceptive measures)

• Body mass index (BMI) greater than or equal to 18 and less than or equal to 32, inclusive

• Hemoglobin greater than or equal to 11.5g/dL

Exclusion Criteria:

• Recent participation (within 28 days) in other research studies

• Recent significant blood donation or plasma donation

• Pregnant or lactating

• Test positive at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg), or hepatitis C virus (HCV)

• Recent (2-year) history or evidence of alcoholism or drug abuse

• History or presence of significant cardiovascular, pulmonary, hepatic, gallbladder or biliary tract, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or psychiatric disease

• Subjects who have used any drugs or substances known to inhibit or induce cytochrome (CYP) P450 enzymes and/or P-glycoprotein (P-gp) within 28 days prior to the first dose and throughout the study

• Drug allergies to colchicine

• Intolerance or food allergy to Seville orange juice

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	PRACS Institute, Ltd. - Cetero Research	Fargo	North Dakota	United States	58104

Sponsors and Collaborators

• Mutual Pharmaceutical Company, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Recalls, Market Withdrawals and Safety Alerts
• Daily Med - Posting of Recently Submitted Labeling to the FDA

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00960193
• Other Study ID Numbers: MPC-004-08-1018
• First Posted: Aug 17, 2009
• Last Update Posted: Jun 8, 2011
• Last Verified: Jun 1, 2011

• Keywords provided by , ,: blood levels over time; colchicine; seville orange juice; pharmacokinetics
• Additional relevant MeSH terms: Colchicine

Study Results

Participant Flow

Arm/Group Title	Colchicine Alone, Colchicine With Seville Orange Juice
Arm/Group Description	On the morning of Day 1, subjects received a single dose of colchicine 0.6 mg after an overnight fast, followed by a 14 day washout period. On Days 15-17, each subject received one 240 ml serving of Seville orange juice in the morning and evening. On Day 18, subjects received one dose of colchicine 0.6 mg in the morning along with a 240 ml serving of Seville orange juice. Subjects received a final 240 ml serving of Seville orange juice in the evening on Day 18.
Period Title: Colchicine Alone
STARTED	24
COMPLETED	24
NOT COMPLETED	0
Period Title: Colchicine Alone
STARTED	24
COMPLETED	23
NOT COMPLETED	1
Period Title: Colchicine Alone
STARTED	23
COMPLETED	23
NOT COMPLETED	0
Period Title: Colchicine Alone
STARTED	23
COMPLETED	23
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Colchicine Alone, Colchicine With Seville Orange Juice
Arm/Group Description	On the morning of Day 1, subjects received a single dose of colchicine 0.6 mg after an overnight fast, followed by a 14 day washout period. On Days 15-17, each subject received one 240 ml serving of Seville orange juice in the morning and evening. On Day 18, subjects received one dose of colchicine 0.6 mg in the morning along with a 240 ml serving of Seville orange juice. Subjects received a final 240 ml serving of Seville orange juice in the evening on Day 18.
Overall Participants	24
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	24 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.83 (7.73)
Sex: Female, Male (Count of Participants)
Female	15 62.5%
Male	9 37.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	24 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	24 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	24 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) of Colchicine
Description	The maximum or peak concentration that colchicine reaches in the plasma.
Time Frame	serial pharmacokinetic blood samples drawn immediately prior to colchicine dosing on Days 1 and 18, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after colchicine dose administration.

Outcome Measure Data

Analysis Population Description

24 subjects were enrolled in this study. One subject was withdrawn due to failure to arrive for the Day 15 orange juice dose.

Arm/Group Title	Colchicine Alone	Colchicine With Seville Orange Juice
Arm/Group Description	Each subject received one 0.6 mg colchicine tablet on Day 1 after an overnight fast, followed by a washout period of 14 days.	On Days 15 to 17, each subject received one 240 ml serving of Seville orange juice in the morning and evening. Then, on Day 18, each subject received one 0.6 mg colchicine tablet and one 240 ml serving of Seville orange juice in the morning after an overnight fast. A final 240 ml serving of Seville orange juice was administered in the evening on Day 18.
Measure Participants	23	23
Mean (Standard Deviation) [pg/mL]	2,328.44 (980.15)	1,668.33 (423.36)

2. Primary Outcome

Title	Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)]
Description	The area under the plasma concentration versus time curve, from time 0 to the time of the last measurable colchicine concentration (t), as calculated by the linear trapezoidal rule.
Time Frame	Serial pharmacokinetic blood samples drawn immediately prior to colchicine dosing on Days 1 and 18, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after colchicine dose administration.

Outcome Measure Data

Analysis Population Description

24 subjects were enrolled in this study. One subject was withdrawn due to failure to arrive for the Day 15 orange juice dose.

Arm/Group Title	Colchicine Alone	Colchicine With Seville Orange Juice
Arm/Group Description	Each subject received one 0.6 mg colchicine tablet on Day 1 after an overnight fast, followed by a washout period of 14 days.	On Days 15 to 17, each subject received one 240 ml serving of Seville orange juice in the morning and evening. Then, on Day 18, each subject received one 0.6 mg colchicine tablet and one 240 ml serving of Seville orange juice in the morning after an overnight fast. A final 240 ml serving of Seville orange juice was administered in the evening on Day 18.
Measure Participants	23	23
Mean (Standard Deviation) [pg*hr/mL]	10,261.93 (4,307.62)	7,634.86 (2,678.60)

3. Primary Outcome

Title	Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]
Description	The area under the plasma concentration versus time curve from time 0 to infinity. AUC(0-∞) was calculated as the sum of AUC(0-t) plus the ratio of the last measurable colchicine plasma concentration to the elimination rate constant.
Time Frame	Serial pharmacokinetic blood samples drawn immediately prior to colchicine dosing on Days 1 and 18, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after colchicine dose administration.

Outcome Measure Data

Analysis Population Description

24 subjects were enrolled in this study. One subject was withdrawn due to failure to arrive for the Day 15 orange juice dose. The pharmacokinetic parameter, AUC(0-∞), could not be determined for 1 subject in the Colchicine Alone group and for 2 subjects in the Colchicine with Seville orange juice group.

Arm/Group Title	Colchicine Alone	Colchicine With Seville Orange Juice
Arm/Group Description	Each subject received one 0.6 mg colchicine tablet on Day 1 after an overnight fast, followed by a washout period of 14 days.	On Days 15 to 17, each subject received one 240 ml serving of Seville orange juice in the morning and evening. Then, on Day 18, each subject received one 0.6 mg colchicine tablet and one 240 ml serving of Seville orange juice in the morning after an overnight fast. A final 240 ml serving of Seville orange juice was administered in the evening on Day 18.
Measure Participants	22	21
Mean (Standard Deviation) [pg*hr/mL]	12,071.30 (4,657.94)	9,148.05 (2,743.54)

Adverse Events

Adverse Event Reporting Description	24 subjects were enrolled in this study. One subject was withdrawn from the study due to failure to arrive for the Day 15 Seville orange juice dose.
Arm/Group Title	Colchicine Alone		Seville Orange Juice Alone		Colchicine With Seville Orange Juice
Arm/Group Description	Each subject received one 0.6 mg colchicine tablet on Day 1 at after an overnight fast, followed by a washout period of 14 days.		On Days 15 to 17, each subject received one 240 ml serving of Seville orange juice in the morning and evening.		On Day 18, each subject received one 0.6 mg colchicine tablet and one 240 ml serving of Seville orange juice after an overnight fast. A final 240 ml serving of Seville orange juice was administered in the evening on Day 18.
All Cause Mortality
	Colchicine Alone		Seville Orange Juice Alone		Colchicine With Seville Orange Juice
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Colchicine Alone		Seville Orange Juice Alone		Colchicine With Seville Orange Juice
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/23 (0%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	Colchicine Alone		Seville Orange Juice Alone		Colchicine With Seville Orange Juice
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/24 (20.8%)		0/23 (0%)		1/23 (4.3%)
Gastrointestinal disorders
Diarrhea	1/24 (4.2%)	1	0/23 (0%)	0	0/23 (0%)	0
Dyspepsia	1/24 (4.2%)	1	0/23 (0%)	0	0/23 (0%)	0
General disorders
Pain	1/24 (4.2%)	1	0/23 (0%)	0	0/23 (0%)	0
Fever	1/24 (4.2%)	1	0/23 (0%)	0	0/23 (0%)	0
Nervous system disorders
Headache	2/24 (8.3%)	2	0/23 (0%)	0	1/23 (4.3%)	1
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain	0/24 (0%)	0	0/23 (0%)	0	1/23 (4.3%)	1
Cough	2/24 (8.3%)	2	0/23 (0%)	0	0/23 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.