Healthy
Conditions
Keywords
bioequivalence, fasting, fed, healthy
Brief summary
This randomized, single dose, three-way crossover study will evaluate the bioequivalence of two formulations of colchicine, the test product (colchicine 0.6mg Mutual) and a marketed combination product (colchicine 0.5 mg with probenecid 500 mg), administered under fasting conditions. It will also determine the bioavailability following a standard high-fat meal and evaluate the safety and tolerability of the test product.
Detailed description
This randomized, single dose, three-way crossover study will evaluate the bioequivalence of two formulations of colchicine, the test product (colchicine 0.6mg Mutual) and a marketed combination product (colchicine 0.5mg with probenecid 500mg), administered under fasting conditions. It will also determine the bioavailability of the test product following a standard high-fat meal and evaluate the safety and tolerability of the test product. Twenty-eight healthy, non-smoking, non-obese (BMI 81-30 kg/m2 and BW ≥110 lbs), 18-45 year old, male and female volunteers will be randomly assigned in a crossover fashion to receive one of three dosing regimens in sequence with washout periods of at least 14 days between dosing periods. After a fast of at least 10 hours, subjects will receive either, one tablet of colchicine 0.6 mg, one tablet of colchicine 0.6 mg after a standardized high-fat,high-calorie breakfast or 0.5mg/500mg colchicine/probenecid. All doses will be given with 240mL of room temperature water. Patients will be confined for at least 15 hours before and 24 hours after each dose with daily outpatient visits over the following 3 days. Blood will be drawn at times sufficient to adequately define the concentration time curves for each dosing regimen, which will be compared to assess the bioequivalence of the reference and test products and the effect of food on the test product. Subjects will also be monitored for adverse events throughout this same period.
Interventions
DRUGColchicine
0.6mg tablet administered after a fast of at least 10 hours
DRUGColchicine/Probenecid
0.5mg/500mg tablet administered after a fast of at least 10 hours
Sponsors
Mutual Pharmaceutical Company, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy adult volunteers, male and female, 18 to 45 years of age, inclusive, with BMI between 18-30 kg/m2, inclusive, and weighing at least 110 pounds. * Female volunteers must be postmenopausal, surgically sterile, or must commit to abstain from heterosexual contact or to use two methods of reliable birth control.
Exclusion criteria
* Subjects who report receiving any investigational drug within 28 days prior to initiation of dosing. * Subjects who report presence or history of significant cardiovascular, respiratory, renal, gastrointestinal, immunologic, hematologic, endocrine, neurologic, or psychiatric disease. * Subjects with clinical lab results outside accepted reference range, or reactive screen for hepatitis B surface antigen, hepatitis C antibody, or HIV antibody. * Subjects who report a history of allergies to colchicine or related drugs, or history of other clinically significant allergies including drug allergies. * Subjects who report a clinically significant illness during the 4 weeks prior to initiation of dosing. * Subjects who report a history of drug or alcohol addiction or abuse within the past year, or who demonstrate a positive drug abuse screen. * Subjects who currently use or have used tobacco products within 6 months prior to dose administration. * Subjects who report donating greater than 150 ml of blood within 28 days or donating plasma within 14 days prior to initiation of dosing. * Subjects who have a positive pregnancy screen, or are currently pregnant or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximal Plasma Concentration (Cmax) | serial pharmacokinetic blood samples collected pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 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 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 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 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 collected pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 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 colchicine plasma concentration to the elimination rate constant. |
Countries
United States
Participant flow
Recruitment details
Twenty-eight (28) 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
75 subjects screened, 47 were screen failures
Participants by arm
| Arm | Count |
|---|---|
| Colchicine(Fasted),Colchicine(Fed),Colchicine/Probenecid All subjects received all study treatments in a randomly assigned sequence of dosing periods. On the morning of Days 1, 15, and 29, each subject received one of the following three treatments: 1) one tablet of colchicine 0.6 mg after an overnight fast of at least 13.5 hours, 2) one tablet of colchicine 0.6 mg after a high-fat breakfast, or 3) one tablet of colchicine 0.5 mg/ probenecid 500 mg following an overnight fast of at least 13.5 hours. | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 14 Day Washout Period A | Physician Decision | 1 |
| Period I | Protocol Violation | 1 |
| Period I | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Colchicine(Fasted),Colchicine(Fed),Colchicine/Probenecid |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants |
| Age Continuous | 23.7 years STANDARD_DEVIATION 5.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Region of Enrollment United States | 28 participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 26 | 3 / 27 | 4 / 27 |
| serious Total, serious adverse events | 0 / 26 | 0 / 27 | 0 / 27 |
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 colchicine plasma concentration to the elimination rate constant.
Time frame: serial pharmacokinetic blood samples collected pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
Population: Colchicine(fasted)-could not be determined for Subject 25. Colchicine(high-fat meal)-could not be determined for Subjects 22,25, and 28. Colchicine/Probenecid(fasted)-could not be determined for Subject 25.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Colchicine 0.6 mg (Fasted) | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 14,112.52 pg-hr/mL |
| Colchicine (High-fat Meal) | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 11,404.09 pg-hr/mL |
| Colchicine 0.5 mg/ Probenecid 500 mg (Fasted) | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 8,481.41 pg-hr/mL |
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 colchicine concentration (t), as calculated by the linear trapezoidal rule.
Time frame: serial pharmacokinetic blood samples collected pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Colchicine 0.6 mg (Fasted) | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 12,588.61 pg-hr/mL |
| Colchicine (High-fat Meal) | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 10,490.95 pg-hr/mL |
| Colchicine 0.5 mg/ Probenecid 500 mg (Fasted) | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 8,090.05 pg-hr/mL |
Primary
Maximal Plasma Concentration (Cmax)
The maximum or peak concentration that colchicine reaches in the plasma.
Time frame: serial pharmacokinetic blood samples collected pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colchicine 0.6 mg (Fasted) | Maximal Plasma Concentration (Cmax) | 2,503.04 pg/mL | Standard Deviation 722.05 |
| Colchicine (High-fat Meal) | Maximal Plasma Concentration (Cmax) | 2,496.88 pg/mL | Standard Deviation 695.09 |
| Colchicine 0.5 mg/ Probenecid 500 mg (Fasted) | Maximal Plasma Concentration (Cmax) | 1,706.03 pg/mL | Standard Deviation 560.73 |