Drug-Drug Interaction Study Between Colchicine and Atorvastatin

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Healthy

Intervention / Treatment
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* Drug: Colchicine
* Drug: Atorvastatin
* 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) 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)

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 0.6 mg colchicine administered alone in the morning on Day 1.<br>|
| Experimental: Colchicine with Atorvastatin<br>Colchicine pharmacokinetics in the presence of atorvastatin at steady state. | Drug: Atorvastatin<br>* Atorvastatin (1 x 40 mg tablet) administered once daily on Days 15-28.<br>Drug: Colchicine<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of Colchicine | The maximum or peak concentration that colchicine reaches in the plasma. | serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration. | 
| Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | The area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration (t), as calculated by the linear trapezoidal rule for colchicine. | Serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration. | 
| Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | The area under the 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 plasma concentration to the elimination rate constant for colchicine. | Serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetics