Clinical trial NCT00984009: A Drug-Food Interaction Study Between Colchicine and Grapefruit Juice
Official title: A One-Directional, Open-Label Drug-Food Interaction Study to Investigate the Effects of Multiple-Daily Consumptions of Grapefruit Juice on the Single-Dose Pharmacokinetics of Colchicine in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pharmacokinetics
Keywords: healthy
pharmacokinetics
grapefruit juice
furanocoumarins
cytochrome p450 3A4
Lead sponsor: Mutual Pharmaceutical Company, Inc.
Sponsor class: INDUSTRY
First posted: 2009-09-24
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: Grapefruit juice is an inhibitor of the cytochrome P450 (CYP) 3A4 enzyme system, one of the enzyme systems responsible for the metabolism of colchicine. This study will evaluate the effect of multiple daily consumptions of grapefruit 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.

Detailed description: Grapefruit juice is an inhibitor of the cytochrome P450 (CYP) 3A4 enzyme system, one of the enzyme systems responsible for the metabolism of colchicine. This study will evaluate the effect of multiple daily consumptions of grapefruit juice on the pharmacokinetic profile of a single 0.6 mg dose of colchicine. On study Day 1, after a fast of at least 10 hours twenty-two 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). 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 on a confined basis at times sufficient to adequately define the pharmacokinetics of colchicine. Blood sampling will continue on a non-confined basis on Days 2-5. 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 dose of grapefruit juice (1 x 240 ml) twice daily. On the morning of Day 18 after a fast of at least 10 hours all subjects will receive a co-administered single oral dose of colchicine (1 x 0.6 mg) and grapefruit 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 on a confined basis at times sufficient to adequately define the pharmacokinetics of colchicine in the presence of grapefruit juice. Blood sampling will continue on a non-confined basis on Days 19-22. Subjects will consume the final administered dose of grapefruit juice (1 x 240 ml) 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.

Eligibility criteria: Inclusion Criteria:

* Healthy adults 18-45 years of age, non-smoking and non-pregnant (post-menopausal, surgically sterile or using effective contraceptive measures) with a body mass index (BMI) greater than or equal to 18 and less than or equal to 32, inclusive.

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

Primary outcomes:
measure: Maximum Plasma Concentration (Cmax)
timeFrame: 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, 24, 36, 48, 72, and 96 hours after colchicine dose administration
measure: Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)]
timeFrame: 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, 24, 36, 48, 72, and 96 hours after colchicine dose administration
measure: Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]
timeFrame: 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, 24, 36, 48, 72, and 96 hours after colchicine dose administration
Secondary outcomes:
Other outcomes:
Locations:
city: Fargo
country: United States
facility: PRACS Institute, Ltd. - Cetero Research
state: North Dakota
Study officials:
affiliation: PRACS - Cetero
name: Anthony R Godfrey, Pharm.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.