Pharmacokinetics
Conditions
Brief summary
Colchicine is a substrate for both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Verapamil hydrochloride is a potent inhibitor of cytochrome P450 (CYP) 3A4 and P-gp. This study will evaluate the effect of multiple doses of extended-release verapamil hydrochloride (verapamil HCl 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). Verapamil hydrochloride is a potent inhibitor of cytochrome P450 (CYP) 3A4 and P-gp. This study will evaluate the effect of multiple doses of extended-release verapamil hydrochloride (verapamil HCl ER) 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 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. After a 14 day washout period, on Day 15 subjects will return to the clinic for dosing of verapamil HCl ER (1 x 240 mg tablet) and a post-dose confinement period of 12 hours. Subjects will return on Days 16-19 for a morning dose of verapamil HCl ER (1 x 240 mg tablet). Verapamil HCl ER doses administered on Days 15-18 will not necessarily be in a fasted state. On the morning of Day 19 after a fast of at least 10 hours, all study participants will receive co-administered single doses of colchicine (1 x 0.6 mg) and verapamil HCl ER (1 x 240 mg). Fasting will continue for 4 hours following these doses and subjects will be confined to the clinic for dosing and for 24 hours after the dose. Blood samples will be drawn at times sufficient to adequately define the pharmacokinetics of colchicine in the presence of verapamil HCL 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. Vital signs (blood pressure and pulse) will be measured pre-dose and 1, 2, and 3 hours post-dose on Day 1, pre-dose and 12 hours post-dose on Day 15, and pre-dose and 1, 2 ,3 and 12 hours post-dose on Day 19 to coincide with peak plasma concentrations of both colchicine and verapamil HCl ER. 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 8am on Day 1 after an overnight fast of at least 10 hours.
DRUGVerapamil HCl ER
One 240 mg verapamil HCl ER tablet taken at 8am on Days 15-18 without regard to meals and along with colchicine at 8am on Day 19 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 verapamil
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) | On Days 1 and 19 - serial pharmacokinetic blood samples were collected pre-dose and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 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)] | On Days 1 and 19 - serial pharmacokinetic blood samples were collected pre-dose and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours post-dose. | The area under the 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-∞)] | On Days 1 and 19 - serial pharmacokinetic blood samples were collected pre-dose and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 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-four (24) healthy, non-smoking, adult male and female volunteers consisting of the community at large were enrolled.
Pre-assignment details
Forty-four (44) subjects were screened, thirteen (13) were screen failures, five (5) were transferred to a different study, one (1) did not appear at check in at Period 1 and one (1) was not needed for the study.
Participants by arm
| Arm | Count |
|---|---|
| Colchicine Alone, Colchicine With Verapamil HCl ER All subjects received each of the study treatments. At 8am on Day 1 after a 10 hour fast all subjects received a single dose of colchicine 0.6 mg followed by a 14 day washout period. At 8am on Days 15-18 all subjects received a dose of verapamil hydrochloride extended-release (verapamil HCl ER) 240 mg without regard to meals. At 8am on Day 19 after a fast of at least 10 hours all subjects received a single dose of colchicine 0.6 mg along with the final dose of verapamil HCl ER 240 mg. | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | Colchicine Alone, Colchicine With Verapamil HCl ER |
|---|---|
| Age Continuous | 27.75 years STANDARD_DEVIATION 9.15 |
| Age, Customized <=18 years | 2 participants |
| Age, Customized >=65 years | 0 participants |
| Age, Customized Between 18 and 65 years | 22 participants |
| 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 | 0 Participants |
| Race (NIH/OMB) Asian | 1 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 | 18 Participants |
| Sex: Female, Male Male | 6 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 / — | 9 / — | 5 / — |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 | 0 / 24 |
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: On Days 1 and 19 - serial pharmacokinetic blood samples were collected pre-dose and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours post-dose.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Colchicine Alone | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 15,371.17 pg-hr/mL |
| Colchicine With Verapamil HCl ER | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 30,586.33 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 beginning from the first dose (time 0) to the last measurable colchicine concentration (time t), as calculated by the linear trapezoidal method.
Time frame: On Days 1 and 19 - serial pharmacokinetic blood samples were collected pre-dose and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours post-dose.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Colchicine Alone | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 13,085.26 pg-hr/mL |
| Colchicine With Verapamil HCl ER | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 24,637.91 pg-hr/mL |
Primary
Maximum Plasma Concentration (Cmax)
The maximum or peak concentration that colchicine reaches in the plasma.
Time frame: On Days 1 and 19 - serial pharmacokinetic blood samples were collected pre-dose and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours post-dose.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Colchicine Alone | Maximum Plasma Concentration (Cmax) | 2,968.42 pg/mL |
| Colchicine With Verapamil HCl ER | Maximum Plasma Concentration (Cmax) | 3,850.63 pg/mL |