Drug-Food Interaction Study of Seville Orange Juice and Colchicine

• ClinicalTrials.gov Identifier: NCT00960193
• Recruitment Status: Completed
• First Posted: August 17, 2009
• Results First Posted: March 16, 2010
• Last Update Posted: June 8, 2011
• Sponsor: Mutual Pharmaceutical Company, Inc.
• Information provided by: Mutual Pharmaceutical Company, Inc.

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 (Clinical Trial)
• 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: February 2009
• Actual Primary Completion Date: April 2009
• Actual Study Completion Date: April 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 [ 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. ]
   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)] [ 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. ]
   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-∞)] [ 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. ]
   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

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

Criteria

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

United States, North Dakota

PRACS Institute, Ltd. - Cetero Research

Fargo, North Dakota, United States, 58104

Sponsors and Collaborators

Mutual Pharmaceutical Company, Inc.

More Information

Additional Information:

Recalls, Market Withdrawals and Safety Alerts 

Daily Med - Posting of Recently Submitted Labeling to the FDA 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Wason S, DiGiacinto JL, Davis MW. Effects of grapefruit and Seville orange juices on the pharmacokinetic properties of colchicine in healthy subjects. Clin Ther. 2012 Oct;34(10):2161-73. doi: 10.1016/j.clinthera.2012.08.007. Epub 2012 Aug 31.

• Responsible Party: Vice President, Branded Products and Medical Affairs, Mutual Pharmaceutical Company, Inc.
• ClinicalTrials.gov Identifier: NCT00960193
• Other Study ID Numbers: MPC-004-08-1018
• First Posted: August 17, 2009
• Results First Posted: March 16, 2010
• Last Update Posted: June 8, 2011
• Last Verified: June 2011

Keywords provided by Mutual Pharmaceutical Company, Inc.:

blood levels over time; colchicine; seville orange juice; pharmacokinetics

Additional relevant MeSH terms:

Colchicine; Gout Suppressants; Antirheumatic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents