Pharmacokinetics
Conditions
Keywords
healthy
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.
Interventions
DRUGColchicine
two 0.6 mg capsules (1.2 mg dose) followed by an additional 0.6mg capsule every hour for 6 additional doses
DRUGMoxifloxacin
400 mg capsule at the 6 hour point
Sponsors
Mutual Pharmaceutical Company, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Eighteen (18) healthy, non-smoking, adult male and female volunteers, consisting of university students and members of the community at large, were to be enrolled.
Pre-assignment details
50 subjects screened, 28 were screen failures, 4 were alternates
Participants by arm
| Arm | Count |
|---|---|
| Colchicine 1.2mg initially (two 0.6 mg capsules) followed by an additional 0.6mg capsule every hour for 6 additional doses \[4.8mg over 6 hours\] | 15 |
| Moxifloxacin 400 mg capsule at the 6 hour point | 3 |
| Total | 18 |
Baseline characteristics
| Characteristic | Moxifloxacin | Total | Colchicine |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0.0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0.0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 18.0 Participants | 15 Participants |
| Age Continuous | 21.3 years STANDARD_DEVIATION 0.6 | 28.7 years STANDARD_DEVIATION 10 | 30.1 years STANDARD_DEVIATION 10.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1.0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0.0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1.0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0.0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0.0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0.0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 16.0 Participants | 13 Participants |
| Region of Enrollment United States | 3 participants | 18.0 participants | 15 participants |
| Sex: Female, Male Female | 1 Participants | 8.0 Participants | 7 Participants |
| Sex: Female, Male Male | 2 Participants | 10.0 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 15 | 0 / 3 |
| serious Total, serious adverse events | 0 / 15 | 0 / 3 |
Outcome results
Primary
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.
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colchicine | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 118.20 ng-hr/mL | Standard Deviation 26.01 |
Primary
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.
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colchicine | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 104.95 ng-hr/mL | Standard Deviation 24.61 |
Primary
Maximum Plasma Concentration (Cmax)
The maximum or peak concentration that colchicine reaches in the plasma.
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colchicine | Maximum Plasma Concentration (Cmax) | 6.84 ng/mL | Standard Deviation 1.3 |
Secondary
Electrocardiogram (ECG) Evaluation of the QTcF Interval (Colchicine)
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.
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colchicine | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Colchicine) | 401.62 milliseconds | Standard Deviation 20.18 |
| Hour 1 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Colchicine) | 397.80 milliseconds | Standard Deviation 19.63 |
| Hour 3 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Colchicine) | 401.76 milliseconds | Standard Deviation 20.04 |
| Hour 6 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Colchicine) | 394.73 milliseconds | Standard Deviation 10.72 |
| Hour 7 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Colchicine) | 388.84 milliseconds | Standard Deviation 15.57 |
| Hour 8 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Colchicine) | 393.93 milliseconds | Standard Deviation 16.3 |
| Hour 10 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Colchicine) | 396.02 milliseconds | Standard Deviation 16.15 |
| Hour 12 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Colchicine) | 396.89 milliseconds | Standard Deviation 11.85 |
| Hour 23 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Colchicine) | 399.36 milliseconds | Standard Deviation 17.38 |
Secondary
Electrocardiogram (ECG) Evaluation of the QTcF Interval (Moxifloxacin)
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.
Time frame: 24 hours - measured 0.5 hr prior to dose (baseline), then 1, 3, 6, 7, 8, 10, 12, and 23 hours after dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colchicine | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Moxifloxacin) | 402.11 milliseconds | Standard Deviation 12.04 |
| Hour 1 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Moxifloxacin) | 398.89 milliseconds | Standard Deviation 1.65 |
| Hour 3 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Moxifloxacin) | 403.67 milliseconds | Standard Deviation 17.91 |
| Hour 6 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Moxifloxacin) | 397.00 milliseconds | Standard Deviation 8.46 |
| Hour 7 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Moxifloxacin) | 397.89 milliseconds | Standard Deviation 8.31 |
| Hour 8 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Moxifloxacin) | 397.44 milliseconds | Standard Deviation 2.59 |
| Hour 10 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Moxifloxacin) | 402.67 milliseconds | Standard Deviation 13.23 |
| Hour 12 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Moxifloxacin) | 405.22 milliseconds | Standard Deviation 17.64 |
| Hour 23 | Electrocardiogram (ECG) Evaluation of the QTcF Interval (Moxifloxacin) | 416.00 milliseconds | Standard Deviation 13.68 |