Drug-Drug Interaction Study Between Colchicine and Ketoconazole

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Pharmacokinetics

Intervention / Treatment
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* Drug: Colchicine
* Drug: Ketoconazole
* 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 (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

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: Single Group 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 colchicine 0.6 mg administered alone at 7:30 a.m. on Day 1.<br>* Other names: COLCRYS TM;|
| Experimental: Colchicine with Steady-State Ketoconazole<br>-colchicine pharmacokinetics in presence of steady-state ketoconazole | Drug: Ketoconazole<br>* 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<br>Drug: Colchicine<br>* 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<br>|

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 blood samples drawn within 1 hour prior to colchicine dosing (0 hour) on Days 1 and 19, and then 0.5, 1, 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 blood samples drawn within 1 hour prior to colchicine dosing (0 hour) on Days 1 and 19, and then 0.5, 1, 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 blood samples drawn within 1 hour prior to colchicine dosing (0 hour) on Days 1 and 19, and then 0.5, 1, 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;, pharmacokinetics;, healthy adult;, cytochrome p450