Drug-Drug Interaction Study Between Colchicine and Atorvastatin

NCT ID: NCT00960323

Last Updated: 2010-03-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-02-28
• Study Completion Date: 2009-03-31

Brief Summary

Colchicine is a substrate for cytochrome P450 3A4 (CYP3A4). In-vitro studies have indicated that the ortho-and para-hydroxylated metabolites of atorvastatin may be CYP3A4/5 competitive and mechanism-based inhibitors (MBI). This study will evaluate the effect of multiple doses of atorvastatin 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 cytochrome P450 3A4 (CYP3A4). In-vitro studies have indicated that the ortho-and para-hydroxylated metabolites of atorvastatin may be CYP3A4 /5 competitive and mechanism-based inhibitors (MBI). This study will evaluate the effect of multiple doses of atorvastatin 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 oral dose of colchicine (1 x 0.6 mg tablet) on Day 1 after an overnight fast. Blood samples will be drawn from all participants before dosing and for 24 hours post-dose at times sufficient to adequately define the pharmacokinetics of colchicine. After a 14 day washout period, starting on the morning of Day 15 and continuing through Day 27, subjects will return to the clinic for once daily administration of atorvastatin (1 x 40 mg tablet) after an overnight fast. After taking the first dose of atorvastatin on Day 15, subjects will remain in the clinic for 1 hour post-dose administration for observation. On the morning of Day 28 after an overnight fast, all study participants will receive a co-administered single oral dose of colchicine (1 x 0.6 mg tablet) and atorvastatin (1 x 40 mg tablet). Blood samples will be drawn from all participants before dosing and for twenty-four hours post-dose at times sufficient to adequately define the pharmacokinetics of colchicine in the presence of atorvastatin at steady 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. Seated blood pressure and pulse, respiratory rate and temperature will be measured at screening, baseline and upon study discharge. Blood pressure and pulse will also be measured pre-dose and at 1 and 2 hours post-dose on Days 1 and 28 to coincide with peak plasma concentrations of colchicine and atorvastatin. 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

Healthy

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 in the morning on Day 1.

Colchicine with Atorvastatin

Colchicine pharmacokinetics in the presence of atorvastatin at steady state.

Group Type: EXPERIMENTAL

Atorvastatin

Intervention Type: DRUG

Atorvastatin (1 x 40 mg tablet) administered once daily on Days 15-28.

Colchicine

Intervention Type: DRUG

A single dose of 0.6 mg colchicine administered with a single dose of 40 mg atorvastatin in the morning on Day 28 after an overnight fast.

Interventions

Colchicine

A single dose of 0.6 mg colchicine administered alone in the morning on Day 1.

Intervention Type: DRUG

Atorvastatin

Atorvastatin (1 x 40 mg tablet) administered once daily on Days 15-28.

Intervention Type: DRUG

Colchicine

A single dose of 0.6 mg colchicine administered with a single dose of 40 mg atorvastatin in the morning on Day 28 after an overnight fast.

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)
• 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 or atorvastatin or any other HMG-CoA reductase inhibitor agents (i.e. simvastatin, lovastatin, rosuvastatin, fluvastatin, and pravastatin)

• 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.

Locations

PRACS Institute, Ltd. - Cetero Research

Fargo, North Dakota, United States

Countries

United States

References

Davis MW, Wason S. Effect of steady-state atorvastatin on the pharmacokinetics of a single dose of colchicine in healthy adults under fasted conditions. Clin Drug Investig. 2014 Apr;34(4):259-67. doi: 10.1007/s40261-013-0168-8.

Reference Type: DERIVED

PMID: 24452746 (View on PubMed)

Other Identifiers

MPC-004-08-1019

Identifier Type: -

Identifier Source: org_study_id