Drug-Drug Interaction Between Colchicine and Verapamil ER

NCT ID: NCT00983242

Last Updated: 2009-10-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-09-30
• Study Completion Date: 2008-10-31

Brief Summary

Colchicine is a substrate for both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Verapamil hydrochloride is a potent inhibitor of cytochrome P450 (CYP) 3A4 and P-gp. This study will evaluate the effect of multiple doses of extended-release verapamil hydrochloride (verapamil HCl ER) 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

Colchicine is a substrate for both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Verapamil hydrochloride is a potent inhibitor of cytochrome P450 (CYP) 3A4 and P-gp. This study will evaluate the effect of multiple doses of extended-release verapamil hydrochloride (verapamil HCl ER) 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-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). 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 then continue on a non-confined basis on Days 2-5. After a 14 day washout period, on Day 15 subjects will return to the clinic for dosing of verapamil HCl ER (1 x 240 mg tablet) and a post-dose confinement period of 12 hours. Subjects will return on Days 16-19 for a morning dose of verapamil HCl ER (1 x 240 mg tablet). Verapamil HCl ER doses administered on Days 15-18 will not necessarily be in a fasted state. On the morning of Day 19 after a fast of at least 10 hours, all study participants will receive co-administered single doses of colchicine (1 x 0.6 mg) and verapamil HCl ER (1 x 240 mg). Fasting will continue for 4 hours following these doses and subjects will be confined to the clinic for dosing and for 24 hours after the dose. Blood samples will be drawn at times sufficient to adequately define the pharmacokinetics of colchicine in the presence of verapamil HCL at steady state. Blood sampling will continue on a non-confined basis on Days 20-23. 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 pre-dose and 1, 2, and 3 hours post-dose on Day 1, pre-dose and 12 hours post-dose on Day 15, and pre-dose and 1, 2 ,3 and 12 hours post-dose on Day 19 to coincide with peak plasma concentrations of both colchicine and verapamil HCl ER. 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 0.6 mg colchicine administered alone at 8am on Day 1 after an overnight fast of at least 10 hours.

Colchicine with Verapamil HCl ER

colchicine pharmacokinetics in presence of steady-state verapamil

Group Type: EXPERIMENTAL

Verapamil HCl ER

Intervention Type: DRUG

One 240 mg verapamil HCl ER tablet taken at 8am on Days 15-18 without regard to meals and along with colchicine at 8am on Day 19 after an overnight fast of at least 10 hours.

Colchicine

Intervention Type: DRUG

A single dose of 0.6 mg colchicine administered along with verapamil HCL ER at 8 am on Day 19 after an overnight fast of at least 10 hours.

Interventions

Colchicine

A single dose of 0.6 mg colchicine administered alone at 8am on Day 1 after an overnight fast of at least 10 hours.

Intervention Type: DRUG

Verapamil HCl ER

One 240 mg verapamil HCl ER tablet taken at 8am on Days 15-18 without regard to meals and along with colchicine at 8am on Day 19 after an overnight fast of at least 10 hours.

Intervention Type: DRUG

Colchicine

A single dose of 0.6 mg colchicine administered along with verapamil HCL ER at 8 am on Day 19 after an overnight fast of at least 10 hours.

Intervention Type: DRUG

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 verapamil

• 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, PharmD

Role: PRINCIPAL_INVESTIGATOR

PRACS - Cetero

Locations

PRACS Institute, Ltd. - Cetero Research

East Grand Forks, Minnesota, 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-004-08-1014

Identifier Type: -

Identifier Source: org_study_id