Drug-Drug Interaction Study Between Colchicine and Ketoconazole

Phase 1

Completed

Conditions: Pharmacokinetics

Interventions: Drug: Ketoconazole
Drug: Colchicine

Registration Number: NCT00983216

Lead Sponsor: Mutual Pharmaceutical Company, Inc.

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 24

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Colchicine with Steady-State Ketoconazole	Ketoconazole	-colchicine pharmacokinetics in presence of steady-state ketoconazole
Colchicine with Steady-State Ketoconazole	Colchicine	-colchicine pharmacokinetics in presence of steady-state ketoconazole
Colchicine alone	Colchicine	-baseline colchicine pharmacokinetics

Primary Outcome Measures

Name	Time	Method
Maximum Plasma Concentration (Cmax)	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	The maximum or peak concentration that colchicine reaches in the plasma.
Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)]	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	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.
Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]	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	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.