Pharmacokinetics
Conditions
Keywords
healthy;, adult;, blood levels over time
Brief summary
Colchicine is a supressor of hepatic CYP1A2 and theophylline is a sensitive CYP1A2 probe substrate. When the two are co-administered the potential exists for a clinically significant drug interaction. This study aims to determine the effect of steady-state colchicine on the pharmacokinetics of theophylline administered as a single dose. A secondary goal is to evaluate the safety and tolerability of this regimen in healthy volunteers. All study subjects will be monitored for adverse events throughout the entire study period.
Detailed description
Colchicine is a supressor of hepatic CYP1A2 and theophylline is a sensitive CYP1A2 probe substrate. When the two are co-administered the potential exists for a clinically significant drug interaction . This study aims to determine the effect of steady-state colchicine on the pharmacokinetics of theophylline administered as a single dose. After a fast of at least 10 hours, thirty healthy, non-smoking, non-obese, non-pregnant adult volunteers between the ages of 18 and 45 will be given one dose of 300mg (80mg/15ml concentrate) theophylline (theophylline elixir) on Day 1. 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 determine the pharmacokinetics of theophylline. Blood sampling will then continue on a non-confined basis on days 2-3. A four day washout period will be completed after the theophylline dose on Day 1 and prior to administration of the first colchicine dose on Day 5. Participants will return to the clinic on days 5-18 for non-confined dosing of colchicine (0.6mg every 12 hours). Administered dosing on these days will not necessarily be in a fasted state. On Day 19 after a fast of at least 10 hours, all study participants will receive 300mg theophylline (80mg/15ml) and 0.6 mg colchicine (1 x 0.6mg tablet) together. Fasting will continue for 4 hours following these co-administered doses. All subjects will be confined to the clinic for dosing and the following 24-hour period. Blood samples will be drawn at times sufficient to adequately determine the pharmacokinetics of theophylline in the presence of colchicine at steady state. Blood sampling will continue on a non-confined basis on Days 20-21. The final dose of colchicine (1x0.6mg) will be administered to subjects the evening of Day 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. 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, 5 (after the morning dose) 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
DRUGTheophylline
single doses of 300 mg (80 mg/15 ml elixer) administered alone at 7:45 am on Day 1 and then along with colchicine at 7:45 am on Day 19
DRUGColchicine
one 0.6 mg tablet twice daily at 7:45 am and 7:45 pm on Days 5 to 19
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 (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 or donation of plasma * 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, hematological, 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 blood samples drawn within 1 hour prior to theophylline dosing (0 hour) on Days 1 and 19, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after theophylline dose administration | The maximum or peak concentration that theophylline drug 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 within 1 hour prior to theophylline dosing (0 hour) on Days 1 and 19, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after theophylline dose administration | The area under the theophylline plasma concentration versus time curve, from time 0 to the time of the last measurable theophylline 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 within 1 hour prior to theophylline dosing (0 hour) on Days 1 and 19, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after theophylline dose administration | The area under the theophylline 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 theophylline plasma concentration to the elimination rate constant. |
Countries
United States
Participant flow
Recruitment details
Thirty (30) healthy, non-smoking, male and female volunteers, consisting of members of the community at large, were to be enrolled.
Pre-assignment details
44 subjects screened, 6 were screen failures, 8 had schedule conflicts
Participants by arm
| Arm | Count |
|---|---|
| Theophylline Alone / With Colchicine (at Steady State) \[All subjects received each of the study treatments.\] Each subject received a single 300 mg dose of theophylline elixer (80 mg/15 ml concentrate) on Day 1 at 7:45am after an overnight fast of at least 10 hours, followed by a washout period of 4 days. On Days 5 to 18, each subject received one 0.6 mg colchicine tablet twice daily at 7:45am and 7:45pm without regard to meals. Then, on Day 19, each subject received both a single dose of theophylline elixer (80 mg/15 ml concentrate) and one 0.6 mg colchicine tablet at 7:45am after an overnight fast of at least 10 hours. (They also received the final dose of one 0.6 mg colchicine tablet at 7:45 pm.) | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Colchicine Alone | Adverse Event | 2 |
| Theophylline Alone | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Theophylline Alone / With Colchicine (at Steady State) |
|---|---|
| Age, Categorical <=18 years | 2 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants |
| Age Continuous | 25.1 years STANDARD_DEVIATION 5.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 1 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 | 27 Participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 16 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 / — | 15 / — | 6 / — |
| serious Total, serious adverse events | 0 / 30 | 0 / 29 | 0 / 27 |
Outcome results
Primary
Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]
The area under the theophylline 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 theophylline plasma concentration to the elimination rate constant.
Time frame: serial pharmacokinetic blood samples drawn within 1 hour prior to theophylline dosing (0 hour) on Days 1 and 19, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after theophylline dose administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Theophylline Alone | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 127.47 µg-hr/mL | Standard Deviation 42.28 |
| Theophylline With Colchicine (at Steady-state) | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 129.39 µg-hr/mL | Standard Deviation 44.83 |
Primary
Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)]
The area under the theophylline plasma concentration versus time curve, from time 0 to the time of the last measurable theophylline concentration (t), as calculated by the linear trapezoidal rule.
Time frame: serial pharmacokinetic blood samples drawn within 1 hour prior to theophylline dosing (0 hour) on Days 1 and 19, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after theophylline dose administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Theophylline Alone | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 120.80 µg-hr/mL | Standard Deviation 38.73 |
| Theophylline With Colchicine (at Steady-state) | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 121.35 µg-hr/mL | Standard Deviation 40.06 |
Primary
Maximum Plasma Concentration (Cmax)
The maximum or peak concentration that theophylline drug reaches in the plasma.
Time frame: serial pharmacokinetic blood samples drawn within 1 hour prior to theophylline dosing (0 hour) on Days 1 and 19, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after theophylline dose administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Theophylline Alone | Maximum Plasma Concentration (Cmax) | 9.76 µg/mL | Standard Deviation 2.25 |
| Theophylline With Colchicine (at Steady-state) | Maximum Plasma Concentration (Cmax) | 9.79 µg/mL | Standard Deviation 1.87 |