Healthy
Conditions
Keywords
pharmacokinetics, colchicine, theophylline
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 (1x0.6mg twice daily every 12 hours). Administered dosing on these days will not necessarily be in a fasted state. Co-administration of a single 300mg dose of theophylline (80mg/15ml) and colchicine (1x0.6mg) will occur on the morning of Day 19 following a fast of at least 10 hours. Twelve hours later, subjects will receive the last dose of colchicine (1x0.6mg). Blood samples will be drawn from all participants before dosing on Day 19 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 20 and 21. 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
300mg (80mg/15ml elixir)
DRUGcolchicine
colchicine 0.6mg by mouth twice daily on Days 5-19, co-administered with theophylline 300mg (80mg/15ml) on the morning of Day 19
Sponsors
Takeda
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; 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 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 * Subjects who test positive for drugs of abuse or alcohol at screening or check-in * History or presence of significant cardiovascular, pulmonary, hepatic, gallbladder or biliary tract, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease or active sexually transmitted disease * History of neuropathy or muscle disorders, peptic ulcer disease, clinically significant cardiac arrhythmias, seizure disorder, and low white blood cell count or other bone marrow disorders * 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 * History of allergy or sensitivity to colchicine or theophylline or aminophylline * Subjects who have had a tattoo or body piercing within 30 days prior to administration of study drug * Subjects with irritable bowel syndrome, chronic diarrhea or other chronic gastro-intestinal problems * Subjects who are lactose intolerant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach the Maximum Plasma Concentration (Tmax) of Theophylline | Day 1 and Day 19 blood samples drawn pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after dose administration. | The time to each the maximum or peak concentration of theophylline in the plasma, after a single dose on Day 1, and after a single dose on Day 19, following 14 days of colchicine dosing. |
| Maximum Plasma Concentration (Cmax) of Theophylline | Day 1 and Day 19 blood samples drawn pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after dose administration. | The maximum or peak concentration of theophylline in the plasma, after a single dose on Day 1, and after another single dose on Day 19 following 14 days of colchicine dosing. |
| Area Under the Concentration Versus Time Curve From Time 0 to Time of the Last Quantifiable Concentration[AUC(0-t)] | Day 1 and Day 19 blood samples drawn pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 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 theophylline. |
| Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | Day 1 and Day 19 blood samples drawn pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 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 theophylline. |
| Apparent Total Body Clearance (CL/F) of Theophylline | Day 1 and Day 19 blood samples drawn pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after dose administration. | Apparent total body clearance after oral administration, calculated as Dose /(AUC0-∞). |
| Apparent Total Volume of Distribution (Vd/F) of Theophylline | Day 1 and Day 19 blood samples drawn pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after dose administration. | Apparent total volume of distribution after oral administration, calculated as Dose /(AUC0-∞) \* Apparent first-order elimination rate constant \[Kel\]) |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at one investigative site in the USA from 11 June 2012 to 01 July 2012.
Pre-assignment details
Thirty non-smoking, adult male and female volunteers (ages 18 to 45 years) were enrolled in this single group study.
Participants by arm
| Arm | Count |
|---|---|
| Theophylline + Colchicine Theophylline 300 mg, solution, orally, on Day 1, then colchicine 0.6 mg tablets, orally, twice daily on Days 5-18, then theophylline 300 mg, solution, orally together with colchicine 0.6 mg, tablet, orally on Day 19 followed by a last dose of colchicine 0.6 mg, tablet, orally, 12 hours later. | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Patient withdrew consent | 1 |
| Overall Study | Protocol deviation | 1 |
Baseline characteristics
| Characteristic | Theophylline + Colchicine |
|---|---|
| Age Continuous | 31.8 Years STANDARD_DEVIATION 7.8 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 23 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 7 Participants |
| Race/Ethnicity, Customized White | 25 Participants |
| Region of Enrollment United States | 30 Participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 12 Participants |
| Tobacco history Never used tobacco | 26 Participants |
| Tobacco history Past smoker or has used other forms of tobacco | 4 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 | 10 / 30 | 10 / 30 | 10 / 29 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 | 0 / 29 |
Outcome results
Primary
Apparent Total Body Clearance (CL/F) of Theophylline
Apparent total body clearance after oral administration, calculated as Dose /(AUC0-∞).
Time frame: Day 1 and Day 19 blood samples drawn pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after dose administration.
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Theophylline | Apparent Total Body Clearance (CL/F) of Theophylline | 1.832 liters/hour | Standard Deviation 0.5849 |
| Theophylline + Colchicine | Apparent Total Body Clearance (CL/F) of Theophylline | 1.741 liters/hour | Standard Deviation 0.4799 |
Comparison: Analysis of variance (ANOVA) was performed on the log-transformed CL/F to calculate least squares mean (LSM) for each treatment. The ANOVA model included sequence, treatment, and treatment within a sequence as fixed effects, and participant as a random effect. The criterion for demonstrating a lack of a clinically significant interaction is a 90% CI for the ratio for AUC0-t, AUC0-∞, and Cmax to be within the 0.80 to 1.25 interval, representing a maximum of 20% difference between treatments.90% CI: [89.25, 98.92]ANOVA
Primary
Apparent Total Volume of Distribution (Vd/F) of Theophylline
Apparent total volume of distribution after oral administration, calculated as Dose /(AUC0-∞) \* Apparent first-order elimination rate constant \[Kel\])
Time frame: Day 1 and Day 19 blood samples drawn pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after dose administration.
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Theophylline | Apparent Total Volume of Distribution (Vd/F) of Theophylline | 36.21 liters | Standard Deviation 13.03 |
| Theophylline + Colchicine | Apparent Total Volume of Distribution (Vd/F) of Theophylline | 34.44 liters | Standard Deviation 10.39 |
Comparison: Analysis of variance (ANOVA) was performed on the log-transformed Vd/F to calculate least squares mean (LSM) for each treatment. The ANOVA model included sequence, treatment, and treatment within a sequence as fixed effects, and participant as a random effect. The criterion for demonstrating a lack of a clinically significant interaction is a 90% CI for the ratio for AUC0-t, AUC0-∞, and Cmax to be within the 0.80 to 1.25 interval, representing a maximum of 20% difference between treatments.90% CI: [90.97, 106.85]ANOVA
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 theophylline.
Time frame: Day 1 and Day 19 blood samples drawn pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after dose administration.
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Theophylline | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 180.7 hours*μg/mL | Standard Deviation 62.3 |
| Theophylline + Colchicine | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 185.7 hours*μg/mL | Standard Deviation 54.46 |
Comparison: Analysis of variance (ANOVA) was performed on the log-transformed AUC(0-∞) to calculate least squares mean (LSM) for each treatment. The ANOVA model included sequence, treatment, and treatment within a sequence as fixed effects, and participant as a random effect. The criterion for demonstrating a lack of a clinically significant interaction is a 90% CI for the ratio for AUC0-t, AUC0-∞, and Cmax to be within the 0.80 to 1.25 interval, representing a maximum of 20% difference between treatments.90% CI: [101.1, 112.04]ANOVA
Primary
Area Under the Concentration Versus Time Curve From Time 0 to Time of the Last Quantifiable Concentration[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 theophylline.
Time frame: Day 1 and Day 19 blood samples drawn pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after dose administration.
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Theophylline | Area Under the Concentration Versus Time Curve From Time 0 to Time of the Last Quantifiable Concentration[AUC(0-t)] | 155.6 hours*μg/mL | Standard Deviation 34.86 |
| Theophylline + Colchicine | Area Under the Concentration Versus Time Curve From Time 0 to Time of the Last Quantifiable Concentration[AUC(0-t)] | 164.0 hours*μg/mL | Standard Deviation 40.01 |
Comparison: Analysis of variance (ANOVA) was performed on the log-transformed AUC(0-t) to calculate least squares mean (LSM) for each treatment. The ANOVA model included sequence, treatment, and treatment within a sequence as fixed effects, and participant as a random effect. The criterion for demonstrating a lack of a clinically significant interaction is a 90% CI for the ratio for AUC0-t, AUC0-∞, and Cmax to be within the 0.80 to 1.25 interval, representing a maximum of 20% difference between treatments.90% CI: [101.81, 109.59]ANOVA
Primary
Maximum Plasma Concentration (Cmax) of Theophylline
The maximum or peak concentration of theophylline in the plasma, after a single dose on Day 1, and after another single dose on Day 19 following 14 days of colchicine dosing.
Time frame: Day 1 and Day 19 blood samples drawn pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after dose administration.
Population: The pharmacokinetic (PK) population is defined as any participant who took a single dose of study medication and had sufficient blood sampling to characterize the non-compartmental PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Theophylline | Maximum Plasma Concentration (Cmax) of Theophylline | 11.0 μg/mL | Standard Deviation 2.16 |
| Theophylline + Colchicine | Maximum Plasma Concentration (Cmax) of Theophylline | 11.7 μg/mL | Standard Deviation 2.79 |
Comparison: Analysis of variance (ANOVA) was performed on the log-transformed Cmax to calculate least squares mean (LSM) for each treatment. The ANOVA model included sequence, treatment, and treatment within a sequence as fixed effects, and participant as a random effect. The criterion for demonstrating a lack of a clinically significant interaction is a 90% CI for the ratio for AUC0-t, (AUC0-∞), and Cmax to be within the 0.80 to 1.25 interval, representing a maximum of 20% difference between treatments.90% CI: [101.77, 110.12]ANOVA
Primary
Time to Reach the Maximum Plasma Concentration (Tmax) of Theophylline
The time to each the maximum or peak concentration of theophylline in the plasma, after a single dose on Day 1, and after a single dose on Day 19, following 14 days of colchicine dosing.
Time frame: Day 1 and Day 19 blood samples drawn pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after dose administration.
Population: The pharmacokinetic (PK) population is defined as any participant who took a single dose of study medication and had sufficient blood sampling to characterize the non-compartmental PK parameters. Patients with available data are included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Theophylline | Time to Reach the Maximum Plasma Concentration (Tmax) of Theophylline | 1.25 hours |
| Theophylline + Colchicine | Time to Reach the Maximum Plasma Concentration (Tmax) of Theophylline | 1.5 hours |
p-value: 0.5663Wilcoxon (Mann-Whitney)