Drug-Drug Interaction Study of Colchicine and Azithromycin

A One-Directional, Open-Label Drug Interaction Study to Investigate the Effects of Multiple-Dose Azithromycin on Single-Dose Pharmacokinetics of Colchicine in Healthy Volunteers

Azithromycin is a possible weak to moderate inhibitor of CYP3A4, one of the enzymes responsible for the metabolism of colchicine. This study will evaluate the effect of multiple doses of azithromycin 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.

Study Overview

• Status: Completed
• Conditions: Pharmacokinetics
• Intervention / Treatment: Drug: Colchicine; Drug: Colchicine; Drug: Azithromycin

Detailed Description

Azithromycin is a possible weak to moderate inhibitor of CYP3A4, one of the enzymes responsible for the metabolism of colchicine. This study will evaluate the effect of multiple doses of azithromycin on the pharmacokinetic profile of a single 0.6 mg dose of colchicine. On 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 a single oral dose of colchicine 0.6 mg. 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. After a 2 week washout period, beginning on Day 15 and continuing through day 18, subjects will return to the clinic daily for non-confined dosing of azithromycin given orally 2 x 250 mg tablets on Day 15 followed by 1 x 250 mg tablet on Days 16-18. Administered azithromycin doses on these days will not necessarily be in a fasted state. On Day 15 after taking the first dose of azithromycin, subjects will remain in the clinic for observation for 1 hour post-dose administration. On Day 19, after a fast of at least 10 hours, all study subjects will receive a co-administered single dose of colchicine (0.6 mg) and azithromycin (1 x 250 mg tablet). All subjects will be confined to the clinic for the 24-hour period following the dose. Blood will be drawn at time sufficient to define the pharmacokinetics of colchicine in the presence of azithromycin 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. 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 19. 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 Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy adults 18-45 years of age, non-smoking and non-pregnant (postmenopausal, 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
• 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, gall bladder or biliary tract, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Colchicine alone; baseline colchicine pharmacokinetics	Drug: Colchicine; A single dose of 0.6 mg colchicine administered alone at 7:30 am on Day 1; Other Names: COLCRYS™; Drug: Colchicine; A single dose of 0.6 mg colchicine administered with azithromycin at 7:30 am on Day 19.; Other Names: COLCRYS™
Experimental: Colchicine with steady-state Azithromycin; colchicine pharmacokinetics in presence of steady-state azithromycin	Drug: Colchicine; A single dose of 0.6 mg colchicine administered alone at 7:30 am on Day 1; Other Names: COLCRYS™; Drug: Colchicine; A single dose of 0.6 mg colchicine administered with azithromycin at 7:30 am on Day 19.; Other Names: COLCRYS™; Drug: Azithromycin; Two 250 mg azithromycin tablets administered at 7:30 am on Day 15, then one 250 mg tablet administered daily at 7:30 am on Days 16 to 19.; Other Names: Zithromax® Tablets USP, 250 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Plasma Concentration (Cmax)	The maximum or peak concentration that colchicine reaches in the plasma.	serial pharmacokinetic plasma concentrations were drawn prior to colchicine dose administration (0 hour) on Days 1 and 19, then at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after colchicine dose administration
Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)]	The area under the colchicine 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.	serial pharmacokinetic plasma concentrations were drawn prior to colchicine dose administration (0 hour) on Days 1 and 19, then at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after colchicine dose administration
Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]	The area under the colchicine 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.	serial pharmacokinetic plasma concentrations were drawn prior to colchicine dose administration (0 hour) on Days 1 and 19, then at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after colchicine dose administration

Collaborators and Investigators

• Sponsor: Mutual Pharmaceutical Company, Inc.
• Investigators: Principal Investigator: Anthony R Godfrey, Pharm.D., PRACS - Cetero

Publications and helpful links

General Publications

• 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. Erratum In: Arthritis Rheum. 2011 Nov;63(11):3521. Dosage error in article text.

Helpful Links

• Recalls, Market Withdrawals and Safety Alerts
• Daily Med - Posting of Recently Submitted Labeling to the FDA

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): August 1, 2008

Study Registration Dates

• First Submitted: August 13, 2009
• First Submitted That Met QC Criteria: August 13, 2009
• First Posted (Estimate): September 24, 2009

Study Record Updates

• Last Update Posted (Estimate): October 28, 2009
• Last Update Submitted That Met QC Criteria: October 20, 2009
• Last Verified: October 1, 2009

More Information

Terms related to this study

• Keywords: healthy; blood levels over time;; colchicine;; azithromycin
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antirheumatic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Anti-Bacterial Agents; Gout Suppressants; Colchicine; Azithromycin
• Other Study ID Numbers: MPC-004-08-1011