Healthy, Pharmacokinetics
Conditions
Keywords
healthy, adult, colchicine, cyclosporine, blood levels over time
Brief summary
Colchicine is a substrate for both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Cyclosporine is a potent inhibitor of both CYP3A4 and P-gp. This study will evaluate the effect of single-dose cyclosporine 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
Colchicine is a substrate for both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Cyclosporine is a potent inhibitor of both CYP3A4 and P-gp. This study will evaluate the effect of single-dose cyclosporine on the pharmacokinetic profile of a single 0.6 mg dose of colchicine. On study 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 one oral dose of colchicine (1 x 0.6 mg tablet). Fasting will continue for 4 hours after the dose. Blood samples will be drawn from all participants before dosing and for 24 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. A 14 day washout period will be completed after the first dose of colchicine on Day 1. On Day 15 after a fast of at least 10 hours, all study participants will receive co-administered single oral doses of colchicine (1 x 0.6 mg tablet) and cyclosporine (1 x 100 mg capsule). Fasting will continue for 4 hours after the dose. Subjects will be confined to the clinic for dosing and a 24 hour period after the dose. Blood samples will be drawn from all participants before dosing and during the 24 hour post-dose period at times sufficient to adequately determine the pharmacokinetics of colchicine. Blood sampling will continue on a non-confined basis on Days 16-19. 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. Vital signs (blood pressure and pulse) will be measured prior to dosing and at 1, 2, and 3 hours following drug administration on Days 1 and 15 to coincide with peak plasma concentrations of both colchicine and cyclosporine. 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 7:15 a.m. on Day 1 after an overnight fast of at least 10 hours.
DRUGCyclosporine
A single dose of 100 mg cyclosporine administered with colchicine at 7:15 a.m. on Day 15 after an overnight fast of at least 10 hours.
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 adults 18-45 years of age, non-smoking and non-pregnant (post-menopausal, 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 or plasma 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, gallbladder or biliary tract, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, 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 * Drug allergies to colchicine or cyclosporine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) | serial pharmacokinetic blood samples drawn immediately prior to colchicine dosing on Days 1 and 15, and then 0.5, 1, 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 blood samples drawn immediately prior to colchicine dosing on Days 1 and 15, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after colchicine dose administration | 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 drawn immediately prior to colchicine dosing on Days 1 and 15, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after colchicine dose administration | 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-four (24) healthy, non-smoking, male and female volunteers, consisting of volunteers from the community at large, were enrolled in the study.
Pre-assignment details
41 subjects were screened, 11 were screen failures, 4 had schedule conflicts, 1 was transferred to a different study, and 1 was not needed
Participants by arm
| Arm | Count |
|---|---|
| Colchicine Alone / With Cyclosporine \[All subjects received each of the study treatments.\] Each subject received one 0.6 mg colchicine tablet on Day 1 at 7:15 a.m. after an overnight fast, followed by a washout period of 14 days. Then, on Day 15, each subject received both one 0.6 mg colchicine tablet and one 100 mg cyclosporine capsule at 7:15 a.m. after an overnight fast of at least 10 hours. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 14 Day Washout Period | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Colchicine Alone / With Cyclosporine |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age Continuous | 29.0 years STANDARD_DEVIATION 6.9 |
| 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 | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 23 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 |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / — | 4 / — |
| serious Total, serious adverse events | 0 / 24 | 0 / 23 |
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 drawn immediately prior to colchicine dosing on Days 1 and 15, and then 0.5, 1, 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-∞)] | 14,996.79 pg-hr/mL |
| Colchicine With Cyclosporine | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 47,312.02 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 drawn immediately prior to colchicine dosing on Days 1 and 15, and then 0.5, 1, 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)] | 12,545.04 pg-hr/mL |
| Colchicine With Cyclosporine | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 39,828.11 pg-hr/mL |
Primary
Maximum Plasma Concentration (Cmax)
The maximum or peak concentration that colchicine reaches in the plasma.
Time frame: serial pharmacokinetic blood samples drawn immediately prior to colchicine dosing on Days 1 and 15, and then 0.5, 1, 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) | 2,720.04 pg/mL |
| Colchicine With Cyclosporine | Maximum Plasma Concentration (Cmax) | 8,817.48 pg/mL |