Healthy; Adult; Volunteer; Colchicine; Pharmacokinetics; Diltiazem; Cytochrome p450 3A4; P-glycoprotein
Conditions
Keywords
healthy; adult; volunteer; colchicine; diltiazem; blood levels over time
Brief summary
Colchicine is a substrate for both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Extended-release diltiazem (diltiazem ER) is a potent inhibitor of both CYP3A4 and P-gp. This study will evaluate the effect of multiple doses of diltiazem ER 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). Extended-release diltiazem (diltiazem ER) is a potent inhibitor of both CYP3A4 and P-gp. This study will evaluate the effect of multiple doses of diltiazem ER on the pharmacokinetic profile of a single 0.6mg 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 (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 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 at 36, 48, 72, and 96 hours post-dose. After a 14-day washout period, beginning on Day 15 and continuing through Day 20 all subjects will return to the clinic for non-confined dosing of diltiazem ER (1 x 240 mg capsule daily). Administered diltiazem ER doses on these days will not necessarily be in a fasted state. On Day 21 after a fast of at least 10 hours, all study participants will receive a co-administered single oral dose of colchicine (1 x 0.6 mg tablet) and diltiazem ER (1 x 240 mg capsule). 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 in the presence of diltiazem ER at steady state. Blood sampling will then continue on a non-confined basis at 36, 48, 72, and 96 hours post-dose administration. Fasting will continue for 4 hours following the co-administered dose of colchicine and diltiazem ER. 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 pre-dose and at 1, 2, and 3 hours post-dosing on Day 1, pre-dose and 12 hours post-dosing on Day 15 (subjects will return to the study center for the 12-hour post-dose vital sign measurements), and pre-dose and 1, 2, 3 and 12 hours post-dosing on Day 21 to coincide with peak plasma concentrations of both colchicine and diltiazem. 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 am on Day 1 after an overnight fast of at least 10 hours.
DRUGDiltiazem ER
One 240 mg diltiazem ER capsule administered daily at 7:15 am on Days 15 to 21.
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 diltiazem.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) | serial pharmacokinetic blood samples drawn immediately prior to dosing on Days 1 and 21, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 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 drawn immediately prior to dosing on Days 1 and 21, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after 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 dosing on Days 1 and 21, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after 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 members of the community at large, were enrolled in the study.
Pre-assignment details
53 subjects were screened, 13 were screen failures, 14 had schedule conflicts, 1 transferred to a different study, and 1 was not needed
Participants by arm
| Arm | Count |
|---|---|
| Colchicine Alone / With Diltiazem (at Steady-state) \[All subjects received each of the study treatments.\] Each subject received one 0.6 mg colchicine tablet on Day 1 at 7:15 a.m. after an overnight fast of at least 10 hours, followed by a washout period of 14 days. On Days 15 to 20, each subject received one 240 mg diltiazem ER capsule at 7:15 a.m. Then, on Day 21, each subject received both one 0.6 mg colchicine tablet and one 240 mg diltiazem ER 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 | Withdrawal by Subject | 1 |
| Diltiazem ER Alone | Adverse Event | 1 |
| Diltiazem ER Alone | missed diltiazem dose | 2 |
Baseline characteristics
| Characteristic | Colchicine Alone / With Diltiazem (at Steady-state) |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants |
| Age Continuous | 28.0 years STANDARD_DEVIATION 8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 0 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 | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 15 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 | 6 / — | 9 / — | 4 / — |
| serious Total, serious adverse events | 0 / 24 | 0 / 21 | 0 / 20 |
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 dosing on Days 1 and 21, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after dose administration
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Colchicine Alone | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 12,025.69 pg-hr/mL |
| Colchicine With Diltiazem (at Steady-state) | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 22,485.97 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 dosing on Days 1 and 21, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after dose administration
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Colchicine Alone | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 10,035.57 pg-hr/mL |
| Colchicine With Diltiazem (at Steady-state) | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 17,729.64 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 dosing on Days 1 and 21, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after dose administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colchicine Alone | Maximum Plasma Concentration (Cmax) | 2,172.32 pg/mL | Standard Deviation 868.72 |
| Colchicine With Diltiazem (at Steady-state) | Maximum Plasma Concentration (Cmax) | 2,802.90 pg/mL | — |