Pharmacokinetic and Exploratory Electrocardiogram (ECG) Study

Phase 1

Completed

Conditions: Pharmacokinetics

Interventions: Drug: Colchicine
Drug: Moxifloxacin

Registration Number: NCT01018420

Lead Sponsor: Mutual Pharmaceutical Company, Inc.

Brief Summary: This study will characterize the pharmacokinetics of colchicine after an oral dosing regimen of 4.8 mg over 6 hours. In addition it will compare the electrocardiogram (ECG) changes, if any, from this dosing regimen to that of a single dose of moxifloxacin 400 mg, a positive control for the corrected QT interval (QTc) prolongation.

Detailed Description: This study will characterize the pharmacokinetics of colchicine after an oral dosing regimen of 4.8 mg over 6 hours. In addition, it will determine whether or not there is a trend toward effect of this high dose regimen on the electrocardiogram (ECG), mainly the corrected QT interval (QTc), via comparison to a 400 mg dose of moxifloxacin, a positive control for QTc prolongation. Eighteen healthy, non-smoking, non-obese, non-pregnant adults between the ages of 18 to 55 years of age will be randomized in a double blind fashion to either the colchicine or moxifloxacin treatment groups. On the day prior to the study (Day -1), subjects will receive colchicine and moxifloxacin placebos according to the same schedule and conditions as will be present during the study, and baseline ECG's will be determined by 24 hour 12-lead Holter monitoring. On Day 1, after a minimum 10 hour overnight fast, subjects enrolled in the colchicine treatment group (N=15) will receive two 0.6 mg capsules (plus one dose moxifloxacin placebo) followed by an additional 0.6 mg colchicine dose (plus one dose moxifloxacin placebo) every hour for 6 additional doses; subjects in the moxifloxacin treatment group will receive placebo doses matching the colchicine treatment group over the first 5 hours, then 400 mg moxifloxacin (plus one dose colchicine placebo) at the 6 hour point. Fasting will continue for 4 hours after the first dose at which time a standardized meal will be served. Blood will be drawn from all participants at times sufficient to adequately define the pharmacokinetics of colchicine. During the study, continuous 24-hour ECG monitoring via 12-lead Holter monitor will be performed. Triplicate ECG records will be extracted from 5 minute observation periods throughout the 24 hours post dose. Finally, all study subjects will be monitored for adverse effects throughout the entire study period.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 18

Inclusion Criteria

Healthy adults 18-55 years of age, non smoking and non-pregnant, weighing at least 55kg and within 15% of ideal body weight, with no significant EKG changes

Exclusion Criteria

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, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease
History or family history of congenital long QT syndrome (LQTS) or sudden death possibly related to LQTS
Subjects who have used any drugs or substances known to inhibit or induce cytochrome (CYP) P450 enzymes and/or P-glycoprotein (P-gp) within 30 days prior to the first dose and throughout the study

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Colchicine	Colchicine	-
Moxifloxacin	Moxifloxacin	-

Primary Outcome Measures

Name	Time	Method
Maximum Plasma Concentration (Cmax)	serial pharmacokinetic blood samples collected pre-dose and 1 (prior to second dose), 3 (prior to fourth dose), 6 (prior to final dose), 6.17, 6.33, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 10, 12, 23, 36, 48, 72 and 96 hours post-dose	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 collected pre-dose and 1 (prior to second dose), 3 (prior to fourth dose), 6 (prior to final dose), 6.17, 6.33, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 10, 12, 23, 36, 48, 72 and 96 hours post-dose	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.
Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]	serial pharmacokinetic blood samples collected pre-dose and 1 (prior to second dose), 3 (prior to fourth dose), 6 (prior to final dose), 6.17, 6.33, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 10, 12, 23, 36, 48, 72 and 96 hours post-dose	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.

Secondary Outcome Measures

Name	Time	Method
Electrocardiogram (ECG) Evaluation of the QTcF Interval (Colchicine)	24 hours - measured 0.5 hr prior to first dose (baseline), then 1, 3, 6, 7, 8, 10, 12, and 23 hours after first dose	The QT interval assesses cardiac repolarization and risk for arrhythmias. It is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. It is dependent on heart rate and is corrected (c) to aid interpretation via Fridericia's adjustment (F), and is reported as QTcF.
Electrocardiogram (ECG) Evaluation of the QTcF Interval (Moxifloxacin)	24 hours - measured 0.5 hr prior to dose (baseline), then 1, 3, 6, 7, 8, 10, 12, and 23 hours after dose	The QT interval assesses cardiac repolarization and risk for arrhythmias. It is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. It is dependent on heart rate and is corrected (c) to aid interpretation via Fridericia's adjustment (F), and is reported as QTcF.