Drug-Drug Interaction Study of Colchicine and Azithromycin

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Pharmacokinetics

Intervention / Treatment
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* Drug: Colchicine
* Drug: Azithromycin
* Drug: Colchicine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Colchicine alone<br>baseline colchicine pharmacokinetics | Drug: Colchicine<br>* A single dose of 0.6 mg colchicine administered alone at 7:30 am on Day 1<br>* Other names: COLCRYS™;|
| Experimental: Colchicine with steady-state Azithromycin<br>colchicine pharmacokinetics in presence of steady-state azithromycin | Drug: Azithromycin<br>* 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.<br>* Other names: Zithromax® Tablets USP, 250 mg;Drug: Colchicine<br>* A single dose of 0.6 mg colchicine administered with azithromycin at 7:30 am on Day 19.<br>* Other names: COLCRYS™;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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blood levels over time;, colchicine;, azithromycin;, healthy