Healthy
Conditions
Keywords
pharmacokinetics
Brief summary
Colchicine is a substrate for cytochrome P450 3A4 (CYP3A4). In-vitro studies have indicated that the ortho-and para-hydroxylated metabolites of atorvastatin may be CYP3A4/5 competitive and mechanism-based inhibitors (MBI). This study will evaluate the effect of multiple doses of atorvastatin 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 cytochrome P450 3A4 (CYP3A4). In-vitro studies have indicated that the ortho-and para-hydroxylated metabolites of atorvastatin may be CYP3A4 /5 competitive and mechanism-based inhibitors (MBI). This study will evaluate the effect of multiple doses of atorvastatin on the pharmacokinetic profile of a single 0.6 mg dose of colchicine. 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) on Day 1 after an overnight fast. Blood samples will be drawn from all participants before dosing and for 24 hours post-dose at times sufficient to adequately define the pharmacokinetics of colchicine. After a 14 day washout period, starting on the morning of Day 15 and continuing through Day 27, subjects will return to the clinic for once daily administration of atorvastatin (1 x 40 mg tablet) after an overnight fast. After taking the first dose of atorvastatin on Day 15, subjects will remain in the clinic for 1 hour post-dose administration for observation. On the morning of Day 28 after an overnight fast, all study participants will receive a co-administered single oral dose of colchicine (1 x 0.6 mg tablet) and atorvastatin (1 x 40 mg tablet). Blood samples will be drawn from all participants before dosing and for twenty-four hours post-dose at times sufficient to adequately define the pharmacokinetics of colchicine in the presence of atorvastatin at steady state. 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, respiratory rate and temperature will be measured at screening, baseline and upon study discharge. Blood pressure and pulse will also be measured pre-dose and at 1 and 2 hours post-dose on Days 1 and 28 to coincide with peak plasma concentrations of colchicine and atorvastatin. 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
DRUGAtorvastatin
Atorvastatin (1 x 40 mg tablet) administered once daily on Days 15-28.
DRUGColchicine
A single dose of 0.6 mg colchicine administered alone in the morning on Day 1.
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) * Body mass index (BMI) greater than or equal to 18 and less than or equal to 32, inclusive * Hemoglobin greater than or equal to 11.5g/dL
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 atorvastatin or any other HMG-CoA reductase inhibitor agents (i.e. simvastatin, lovastatin, rosuvastatin, fluvastatin, and pravastatin)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Colchicine | serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 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 prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration. | The area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration (t), as calculated by the linear trapezoidal rule for colchicine. |
| Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | Serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 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 plasma concentration to the elimination rate constant for colchicine. |
Countries
United States
Participant flow
Recruitment details
Forty-two volunteers were screened for participation in this study. Eight were screen failures, four were not needed, four withdrew consent and two had a schedule conflict.
Participants by arm
| Arm | Count |
|---|---|
| Colchicine, Atorvastatin, Colchicine and Atorvastatin On the morning of Day 1, subjects received a single dose of colchicine 0.6 mg after an overnight fast, followed by a 14 day washout period. On the mornings of Days 15-27, subjects received a daily dose of atorvastatin 40 mg after an overnight fast. On the morning of Day 28, subjects received a co-administered single oral dose of colchicine 0.6 mg and atorvastatin 40 mg following an overnight fast. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Atorvastatin Alone | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Colchicine, Atorvastatin, Colchicine and Atorvastatin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age Continuous | 26.29 years STANDARD_DEVIATION 6.46 |
| 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 | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 22 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 22 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 | 4 / 24 | 6 / 24 | 1 / 23 |
| serious Total, serious adverse events | 0 / 24 | 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 plasma concentration to the elimination rate constant for colchicine.
Time frame: Serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration.
Population: 24 subjects were enrolled in this study. One subject withdrew prior to Period II check-in. The pharmacokinetic parameter, AUC(0-∞), could not be determined for 1 subject in the Colchicine Alone group and for 4 subjects in the Colchicine with Atorvastatin group.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Colchicine Alone | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 9,592.53 pg*hr/mL |
| Colchicine With Atorvastatin | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 11,043.58 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 concentration (t), as calculated by the linear trapezoidal rule for colchicine.
Time frame: Serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration.
Population: 24 subjects were enrolled in this study. One subject withdrew from the study prior to Period II check in due to a schedule conflict.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Colchicine Alone | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 8,717.33 pg*hr/mL |
| Colchicine With Atorvastatin | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 10,714.92 pg*hr/mL |
Primary
Maximum Plasma Concentration (Cmax) of Colchicine
The maximum or peak concentration that colchicine reaches in the plasma.
Time frame: serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration.
Population: 24 subjects were enrolled in this study. One subject withdrew from the study prior to Period II check in due to a schedule conflict.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colchicine Alone | Maximum Plasma Concentration (Cmax) of Colchicine | 2,023.29 pg/mL | Standard Deviation 903.14 |
| Colchicine With Atorvastatin | Maximum Plasma Concentration (Cmax) of Colchicine | 2,487.96 pg/mL | Standard Deviation 646.99 |