Pharmacokinetics
Conditions
Keywords
blood levels over time;, colchicine;, azithromycin;, healthy
Brief summary
Azithromycin is a possible weak to moderate inhibitor of CYP3A4, one of the enzymes responsible for the metabolism of colchicine. This study will evaluate the effect of multiple doses of azithromycin 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
Azithromycin is a possible weak to moderate inhibitor of CYP3A4, one of the enzymes responsible for the metabolism of colchicine. This study will evaluate the effect of multiple doses of azithromycin on the pharmacokinetic profile of a single 0.6 mg dose of colchicine. On day 1, 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 will be given a single oral dose of colchicine 0.6 mg. 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. After a 2 week washout period, beginning on Day 15 and continuing through day 18, subjects will return to the clinic daily for non-confined dosing of azithromycin given orally 2 x 250 mg tablets on Day 15 followed by 1 x 250 mg tablet on Days 16-18. Administered azithromycin doses on these days will not necessarily be in a fasted state. On Day 15 after taking the first dose of azithromycin, subjects will remain in the clinic for observation for 1 hour post-dose administration. On Day 19, after a fast of at least 10 hours, all study subjects will receive a co-administered single dose of colchicine (0.6 mg) and azithromycin (1 x 250 mg tablet). All subjects will be confined to the clinic for the 24-hour period following the dose. Blood will be drawn at time sufficient to define the pharmacokinetics of colchicine in the presence of azithromycin at steady state. Blood sampling will continue on a non-confined basis on Days 20-23. 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. Seated blood pressure and pulse will be measured prior to dosing and at approximately 1, 2, and 3 hours following drug administration on Days 1 and 19. 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.
Interventions
DRUGColchicine
A single dose of 0.6 mg colchicine administered alone at 7:30 am on Day 1
DRUGAzithromycin
Two 250 mg azithromycin tablets administered at 7:30 am on Day 15, then one 250 mg tablet administered daily at 7:30 am on Days 16 to 19.
Sponsors
Mutual Pharmaceutical Company, Inc.
Study design
Allocation
NON_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 adults 18-45 years of age, non-smoking and non-pregnant (postmenopausal, 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 * 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, gall bladder or biliary tract, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) | serial pharmacokinetic plasma concentrations were drawn prior to colchicine dose administration (0 hour) on Days 1 and 19, then at 0.5, 1.0, 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 plasma concentrations were drawn prior to colchicine dose administration (0 hour) on Days 1 and 19, then at 0.5, 1.0, 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 plasma concentrations were drawn prior to colchicine dose administration (0 hour) on Days 1 and 19, then at 0.5, 1.0, 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. |
Participant flow
Recruitment details
Twenty-four (24) healthy, non-smoking, male and female volunteers, consisting of members of the community at large, were to be enrolled.
Pre-assignment details
40 subjects screened, 6 were screen failures, 6 had schedule conflicts, 3 transferred to another study, 1 was not needed
Participants by arm
| Arm | Count |
|---|---|
| Colchicine Alone / With Azithromycin (at Steady State) \[All subjects received each of the study treatments.\] Each subject received one 0.6 mg colchicine tablet on Day 1 at 7:30am after an overnight fast, followed by a washout period of 14 days. On Day 15, each subject received two 250 mg azithromycin tablets at 7:30 am after an overnight fast, followed by one 250 mg azithromycin tablet daily at 7:30 am without regard to meals on Days 16 to 18. Then, on Day 19, each subject received both one 0.6 mg colchicine tablet and one 250 mg azithromycin tablet at 7:30 am after an overnight fast. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 14 Day Washout Period | Withdrawal by Subject | 2 |
| Colchicine With Azithromycin | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Colchicine Alone / With Azithromycin (at Steady State) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age Continuous | 27.7 years STANDARD_DEVIATION 8.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 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 | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 14 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 | 8 / — | 5 / — | 4 / — |
| serious Total, serious adverse events | 0 / 24 | 0 / 22 | 0 / 22 |
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 plasma concentrations were drawn prior to colchicine dose administration (0 hour) on Days 1 and 19, then at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after colchicine dose administration
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Colchicine Alone | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 14,125.25 pg-hr/mL |
| Colchicine With Azithromycin (at Steady-state) | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 19,611.01 pg-hr/mL |
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, from time 0 to the time of the last measurable colchicine concentration (t), as calculated by the linear trapezoidal rule.
Time frame: serial pharmacokinetic plasma concentrations were drawn prior to colchicine dose administration (0 hour) on Days 1 and 19, then at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after colchicine dose administration
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Colchicine Alone | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 11,975.72 pg-hr/mL |
| Colchicine With Azithromycin (at Steady-state) | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 17,161.00 pg-hr/mL |
Primary
Maximum Plasma Concentration (Cmax)
The maximum or peak concentration that colchicine reaches in the plasma.
Time frame: serial pharmacokinetic plasma concentrations were drawn prior to colchicine dose administration (0 hour) on Days 1 and 19, then at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after colchicine dose administration
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Colchicine Alone | Maximum Plasma Concentration (Cmax) | 2,737.00 pg/mL |
| Colchicine With Azithromycin (at Steady-state) | Maximum Plasma Concentration (Cmax) | 3,051.76 pg/mL |