Drug-Drug Interaction Study Between Colchicine and Ketoconazole

NCT ID: NCT00983216

Last Updated: 2009-10-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-07-31
• Study Completion Date: 2008-08-31

Brief Summary

Ketoconazole is a potent 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 doses of ketoconazole 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

Ketoconazole is a potent 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 doses of ketoconazole 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. After a fast of at least 10 hours, twenty-four healthy, non-smoking, non-obese, non-pregnant adult volunteers between the ages of 18 and 45 years will be given one dose of colchicine (1 x 0.6 mg tablet) orally on Day 1. Fasting will continue for 4 hours after the dose. Blood samples will be drawn from all participants before dosing and for twenty-four hours post-dose on a confined basis at times sufficient to adequately define the pharmacokinetics of colchicine. Blood sampling will then continue on a non-confined basis on Days 2-5. On Days 15-18, subjects will return to the clinic daily for non-confined dosing of ketoconazole (1 x 200 mg tablet) twice daily, every 12 hours. Administered ketoconazole doses on these days will not necessarily be in a fasted state. On Day 15, after taking the first dose of ketoconazole, subjects will remain in the clinic for observation for 1 hour post-dose administration. Then, on Day 19, co-administration of a single dose of colchicine (1 x 0.6 mg tablet) and ketoconazole (1 x 200 mg tablet) will occur following a fast of at least 10 hours in subjects confined to the clinic for dosing and 24-hour blood sampling will be performed at times sufficient to adequately determine the pharmacokinetics of colchicine. Blood sampling will continue on a non-confined basis on Days 20-23. Fasting will continue for 4 hours following the co-administered dose of ketoconazole and colchicine. The final dose of ketoconazole (1 x 200 mg tablet) will be administered to subjects the evening of Day 19, in a non-fasting state. 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. Vital signs (blood pressure and pulse) will be measured prior to dosing and at 1, 2, and 3 hours following drug administration on Days 1 and 19 to coincide with peak plasma concentrations of both colchicine and ketoconazole. 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.

Conditions

Pharmacokinetics

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Colchicine alone

-baseline colchicine pharmacokinetics

Group Type: ACTIVE_COMPARATOR

Colchicine

Intervention Type: DRUG

A single dose of colchicine 0.6 mg administered alone at 7:30 a.m. on Day 1.

Colchicine with Steady-State Ketoconazole

-colchicine pharmacokinetics in presence of steady-state ketoconazole

Group Type: EXPERIMENTAL

Ketoconazole

Intervention Type: DRUG

one 200 mg Ketoconazole tablet administered twice daily at 7:15 a.m. and 7:15 p.m. on Days 15-18 without regard to meals, then along with colchicine at 7:15 a.m. on Day 19 after an overnight fast of at least 10 hours; final dose of 200 mg administered at 7:15 p.m. on Day 19

Colchicine

Intervention Type: DRUG

A single dose of colchicine 0.6 mg administered along with ketoconazole at 7:15 a.m. on Day 19 after an overnight fast of at least 10 hours

Interventions

Colchicine

A single dose of colchicine 0.6 mg administered alone at 7:30 a.m. on Day 1.

Intervention Type: DRUG

Ketoconazole

one 200 mg Ketoconazole tablet administered twice daily at 7:15 a.m. and 7:15 p.m. on Days 15-18 without regard to meals, then along with colchicine at 7:15 a.m. on Day 19 after an overnight fast of at least 10 hours; final dose of 200 mg administered at 7:15 p.m. on Day 19

Intervention Type: DRUG

Colchicine

A single dose of colchicine 0.6 mg administered along with ketoconazole at 7:15 a.m. on Day 19 after an overnight fast of at least 10 hours

Intervention Type: DRUG

Other Intervention Names

COLCRYS TM

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 or ketoconazole or any other anti-fungal agent

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Mutual Pharmaceutical Company, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Mutual Pharmaceutical Company, Inc.

Principal Investigators

Anthony R Godfrey, Pharm.D.

Role: PRINCIPAL_INVESTIGATOR

PRACS - Cetero

Locations

PRACS Institute, Ltd. - Cetero Research

Fargo, North Dakota, United States

Countries

United States

References

Terkeltaub RA, Furst DE, Digiacinto JL, Kook KA, Davis MW. Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors. Arthritis Rheum. 2011 Aug;63(8):2226-37. doi: 10.1002/art.30389.

Reference Type: DERIVED

PMID: 21480191 (View on PubMed)

Related Links

http://www.fda.gov/opacom/7alerts.html

Recalls, Market Withdrawals and Safety Alerts

http://dailymed.nlm.nih.gov/dailymed/about.cfm

Daily Med - Posting of Recently Submitted Labeling to the FDA

Other Identifiers

MPC-004-08-1012

Identifier Type: -

Identifier Source: org_study_id