Pharmacokinetics
Conditions
Keywords
healthy, pharmacokinetics, drug-drug interaction
Brief summary
Clarithromycin is a potent inhibitor of the activity of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp). CYP 3A4 plays a role in the metabolism of colchicine and P-gp is responsible for the efflux of colchicine across membranes. This study will evaluate the effect of clarithromycin-related inhibition of CYP 3A4 and P-gp on the pharmacokinetics of colchicine. It will also evaluate the safety and tolerability of concurrent administration of clarithromycin and a single dose of colchicine.
Detailed description
Clarithromycin is a potent inhibitor of the activity of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp). CYP 3A4 plays a role in the metabolism of colchicine and P-gp is responsible for the efflux of colchicine across membranes. This open-label, one sequence, two-period, drug-drug interaction study will evaluate the effect of clarithromycin-related inhibition of CYP 3A4 and P-gp on colchicine pharmacokinetics in 24 healthy, non-smoking, non-obese (within +/- 15% of ideal body weight), male and female adult volunteers. The safety and tolerability of concurrent administration of clarithromycin and a single dose of colchicine will also be evaluated. During the first period, subjects will be confined to the study unit beginning the afternoon of the day prior to scheduled dosing (Day -1). On the morning of Day 1, after an overnight fast of at least 10 hours, subjects will be administered a single dose of colchicine 0.6 mg tablet with 240 ml of room temperature water. Blood will be drawn at times sufficient to characterize the baseline pharmacokinetics for this group. Following a 20 day washout period on Day 22, all subjects will return to the clinic to receive a supply of clarithromycin 250 mg tablets, which they will take on an outpatient basis twice daily (at 8 a.m. and 8 p.m.) without regard to meals for a total of 14 doses. Clinic staff will make telephone contact daily with subjects during this course to confirm compliance with the clarithromycin dosing regimen, and to monitor for adverse events and use of concomitant medication. On day 28 in the afternoon, subjects will again be confined to the study unit. On the morning of day 29, after an overnight fast of at least 10 hours all subjects will be administered a single dose of colchicine 0.6 mg and the final dose of clarithromycin with 240 ml water. Blood samples will be drawn at times sufficient to determine pharmacokinetic profiles of colchicine in the presence of clarithromycin at steady state. The pharmacokinetic profiles will be compared to determine the extent of drug-drug interaction.
Interventions
DRUGcolchicine
0.6mg tablet administered at 9am on Day 1
DRUGclarithromycin
250 mg clarithromycin tablet taken on an outpatient basis twice daily at 8am and 8pm for 14 doses (starting with 8pm dose on Day 22 and concluding with 8am dose on Day 29)
Sponsors
Mutual Pharmaceutical Company, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy, non-smoking, adult volunteers, male and female, 18 to 45 years of age, weighing at least 55 kg and within 15% of ideal body weight, with hemoglobin \>/=12 g/dL. * Female volunteers must be sexually abstinent for 14 days prior to the first dose and throughout the study or using acceptable birth control methods (prior to and during the study), including being postmenopausal or surgically sterile (or sexual activity restricted to a partner that is surgically sterile), hormonal contraception, an IUD, or barrier methods with spermicide. Additionally, they will be advised to remain sexually inactive or to keep the same birth control method for at least 14 days following the last dose of colchicine.
Exclusion criteria
* Subjects who are pregnant or lactating * Test positive at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg) or hepatitis C virus (HCV) * Have history or presence of significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or psychiatric disease; have used any drugs or substances known to inhibit or induce CYP enzymes and/or P-gp within 30 days prior to the first dose and throughout the study * Recent (2-year) history of evidence of alcoholism or drug abuse * Subjects who donated 50-499 ml of blood within 30 days and more than 499 ml within 56 days prior to the first dose; subjects who have donated in excess of 500 ml of blood in 14 days, 1500 ml or blood in 180 days, or 2500 ml of blood in 1 year (through completion of the study) * Have participated in another clinical trial within 30 days prior to dosing * Known and documented drug allergies to colchicine or macrolide antibiotics.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) | serial pharmacokinetic blood samples collected immediately prior to dosing on Days 1 and 29, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after 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 collected immediately prior to dosing on Days 1 and 29, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after dose administration | The area under the colchicine plasma concentration versus time curve beginning from the first dose (time 0) to the last measurable colchicine concentration (time t), as calculated by the linear trapezoidal method. |
| Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | serial pharmacokinetic blood samples collected immediately prior to dosing on Days 1 and 29, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after 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. |
Countries
United States
Participant flow
Recruitment details
Twenty-four (24) healthy, non-smoking, adult male and female volunteers, consisting of members of the community at large, were enrolled.
Pre-assignment details
56 subjects screened, 32 were screen failures
Participants by arm
| Arm | Count |
|---|---|
| Colchicine Alone / With Clarithromycin \[All subjects received each of the study treatments.\] Each subject received one colchicine 0.6 mg tablet on Day 1 at 9:00 a.m. after an overnight fast of at least 10 hours, followed by a 21 day washout period. On Day 22, subjects began taking one 250 mg clarithromycin tablet every 12 hours at 8:00 a.m. and 8:00 p.m. for 7 days without regard to meals. Then, on Day 29, each subject received one colchicine 0.6 mg tablet along with final dose of 250 mg clarithromycin at 9:00 a.m. after an overnight fast of at least 10 hours. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Clarithromycin Alone | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Colchicine Alone / With Clarithromycin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age Continuous | 22.3 years STANDARD_DEVIATION 4.1 |
| Race/Ethnicity, Customized Caucasian | 24 participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 11 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 | 7 / — | 5 / — | 4 / — |
| serious Total, serious adverse events | 0 / 24 | 0 / 23 | 0 / 23 |
Outcome results
Primary
Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]
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.
Time frame: serial pharmacokinetic blood samples collected immediately prior to dosing on Days 1 and 29, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after dose administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colchicine Alone | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 15.53 ng-hr/mL | Standard Deviation 7.7 |
| Colchicine With Clarithromycin | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 52.62 ng-hr/mL | Standard Deviation 12.02 |
Primary
Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)]
The area under the colchicine plasma concentration versus time curve beginning from the first dose (time 0) to the last measurable colchicine concentration (time t), as calculated by the linear trapezoidal method.
Time frame: serial pharmacokinetic blood samples collected immediately prior to dosing on Days 1 and 29, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after dose administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colchicine Alone | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 12.37 ng-hr/mL | Standard Deviation 4.66 |
| Colchicine With Clarithromycin | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 41.95 ng-hr/mL | Standard Deviation 9.78 |
Primary
Maximum Plasma Concentration (Cmax)
The maximum or peak concentration that colchicine reaches in the plasma.
Time frame: serial pharmacokinetic blood samples collected immediately prior to dosing on Days 1 and 29, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after dose administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colchicine Alone | Maximum Plasma Concentration (Cmax) | 2.84 ng/mL | Standard Deviation 0.88 |
| Colchicine With Clarithromycin | Maximum Plasma Concentration (Cmax) | 8.44 ng/mL | Standard Deviation 1.49 |