Pharmacokinetics
Conditions
Keywords
healthy, pharmacokinetics, drug-interaction
Brief summary
This study will evaluate the effect, if any, of twice daily dosing of colchicine 0.6 mg at steady state on the steady state pharmacokinetic profile of ethinyl estradiol and norethindrone (Ortho-Novum 1/35). It will also evaluate the effects, if any, of steady state ethinyl estradiol and norethindrone on colchicine at steady state. Finally, this study will assess the safety and tolerability of concurrent use of colchicine and an estrogen/progesterone-containing oral contraceptive.
Detailed description
This study will evaluate the effect, if any, of twice daily dosing of colchicine 0.6 mg at steady state on the steady state pharmacokinetic profile of ethinyl estradiol and norethindrone (Ortho-Novum 1/35). It will also evaluate the effects, if any, of steady state ethinyl estradiol and norethindrone on colchicine at steady state. Finally, this study will assess the safety and tolerability of concurrent use of colchicine and an estrogen/progesterone-containing oral contraceptive. Following an optional single cycle run-in period in which subjects taking other oral contraceptives are switched to Ortho-Novum 1/35, 30 healthy adult female volunteers of child bearing age (18-45 years old) will be randomized in a double blind crossover fashion to receive each of two ethinyl estradiol and norethindrone dosing regimens in sequence. During each of the two dosing periods, subjects will receive one ethinyl estradiol and norethindrone tablet on the mornings of Days 1-7 of their cycles. On days 8-21, subjects will receive twice daily doses of either colchicine (0.6 mg capsule twice daily with breakfast and dinner) or the placebo (one capsule twice daily with breakfast and dinner), according to their randomization schedule, along with one ethinyl estradiol and norethindrone tablet. Subjects will receive the alternate dosing regimen in Cycle 2. Blood samples will be drawn at times sufficient to determine the steady state pharmacokinetics of ethinyl estradiol and norethindrone with and without steady state colchicine. In addition, during the cycle in which active colchicine is given, the effect of steady state ethinyl estradiol and norethindrone on steady state colchicine will be evaluated. Subjects will be monitored for adverse effects throughout the study via query and spontaneous reporting. Additionally baseline 12 lead EKG and vital signs will be compared to those obtained at time points throughout the study period.
Interventions
one tablet daily - 1 mg norethindrone/0.035 mg ethinyl estradiol on Days 1 to 21; inert ingredients on Days 22 to 28
DRUGColchicine
0.6mg tablet every 12 hours on Days 8 to 21
DRUGPlacebo (for Colchicine)
placebo tablet every 12 hours on Days 8 to 21
Sponsors
Mutual Pharmaceutical Company, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy, non-smoking female volunteers of childbearing potential aged 18 to 45 years weighing at least 55 kg and within 15% of ideal body weight who are taking oral contraceptives on the advice of their personal health care provider and willing to switch to Ortho-Novum 1/35 * Subjects should be either sexually inactive or using a double barrier method of contraception for 14 days before the first dose of study drug and throughout the study
Exclusion criteria
* Pregnant or lactating * Recent (2-year) history or evidence of alcoholism or drug abuse * Test positive at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg), or hepatitis C antibody (HCV) * History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease * Hemoglobin \< 12 g/dL * Use of any drugs or substances known to inhibit or induce cytochrome (CYP) P450 enzymes and/or P-gp within 30 days prior to the first dose of Ortho-Novum® 1/35 or expected to require such use
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration of Norethindrone With Colchicine at Steady State (Cmax, ss) | Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose. | The maximum or peak concentration that Norethindrone with Colchicine reaches in the plasma at steady state. Steady state refers to the point that constant concentration of drug is achieved subsequent to administration of constant doses of that drug given at constant intervals. |
| Maximum Plasma Concentration of Norethindrone With Placebo at Steady State (Cmax, ss) | Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose. | The maximum or peak concentration that Norethindrone with Placebo reaches in the plasma at steady state. Steady state refers to the point that constant concentration of drug is achieved subsequent to administration of constant doses of that drug given at constant intervals. |
| Maximum Plasma Concentration of Ethinyl Estradiol With Colchicine at Steady State (Cmax, ss) | Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose. | The maximum or peak concentration that Ethinyl Estradiol with Colchicine reaches in the plasma at steady state. Steady state refers to the point that constant concentration of drug is achieved subsequent to administration of constant doses of that drug given at constant intervals. |
| Maximum Plasma Concentration of Ethinyl Estradiol With Placebo at Steady State (Cmax, ss) | Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose. | The maximum or peak concentration that Ethinyl Estradiol with Placebo reaches in the plasma at steady state. Steady state refers to the point that constant concentration of drug is achieved subsequent to administration of constant doses of that drug given at constant intervals. |
| Maximum Plasma Concentration of Colchicine With Norethindrone/Ethinyl Estradiol at Steady State (Cmax, ss) | Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose | The maximum or peak concentration that Colchicine with Norethindrone/Ethinyl Estradiol reaches in the plasma at steady state. Steady state refers to the point that constant concentration of drug is achieved subsequent to administration of constant doses of that drug given at constant intervals |
| Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] for Norethindrone With Colchicine | Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose. | 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. |
| Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] for Norethindrone With Placebo | Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose. | 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. |
| Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] Ethinyl Estradiol With Colchicine | serial pharmacokinetic plasma concentrations were drawn prior to dose administration (0 hour) and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.33, 2.67, 3, 3.33, 3.67, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 14, 18, 24, 36, and 48 hours after drug 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. |
| Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] for Ethinyl Estradiol With Placebo | Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose. | 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. |
| Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] for Colchicine With Norethindrone/Ethinyl Estradiol | Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose | 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. |
Countries
United States
Participant flow
Recruitment details
Thirty (30) healthy, non-smoking, premenopausal adult female volunteers, consisting of university students and members of the community at large, were to be enrolled.
Pre-assignment details
51 subjects screened, 21 were screen failures
Participants by arm
| Arm | Count |
|---|---|
| Oral Contraceptive With Placebo Then Colchicine All subjects received each of the two study treatments in a randomly assigned sequence of two dosing cycles. On the mornings of Days 1 to 20 of each cycle, each subject took one active tablet of Ortho-Novum 1/35. On Days 8 to 20 of each cycle, subjects additionally took one capsule of study drug (either over-encapsulated colchicine tablets 0.6 mg or a matching placebo capsule) twice daily in the morning and with dinner. On Day 21 of each cycle, subjects received a single dose of study drug and a single active tablet of Ortho-Novum 1/35; then, 12 hours later, they received a second dose of study drug with a light snack. Inert Ortho-Novum 1/35 tablets were taken on Day 22 (after breakfast and the last blood sample). | 15 |
| Oral Contraceptive With Colchicine Then Placebo All subjects received each of the two study treatments in a randomly assigned sequence of two dosing cycles. On the mornings of Days 1 to 20 of each cycle, each subject took one active tablet of Ortho-Novum 1/35. On Days 8 to 20 of each cycle, subjects additionally took one capsule of study drug (either over-encapsulated colchicine tablets 0.6 mg or a matching placebo capsule) twice daily in the morning and with dinner. On Day 21 of each cycle, subjects received a single dose of study drug and a single active tablet of Ortho-Novum 1/35; then, 12 hours later, they received a second dose of study drug with a light snack. Inert Ortho-Novum 1/35 tablets were taken on Day 22 (after breakfast and the last blood sample). | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Oral Contraceptive With Colchicine Then Placebo | Total | Oral Contraceptive With Placebo Then Colchicine |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0.0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0.0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 30.0 Participants | 15 Participants |
| Age Continuous | 23.9 years STANDARD_DEVIATION 4.2 | 23.9 years STANDARD_DEVIATION 6.3 | 23.8 years STANDARD_DEVIATION 7.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0.0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0.0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0.0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0.0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0.0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0.0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 30.0 Participants | 15 Participants |
| Region of Enrollment United States | 15 participants | 30.0 participants | 15 participants |
| Sex: Female, Male Female | 15 Participants | 30.0 Participants | 15 Participants |
| Sex: Female, Male Male | 0 Participants | 0.0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 10 / — |
| serious Total, serious adverse events | 0 / 27 |
Outcome results
Primary
Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] Ethinyl Estradiol With Colchicine
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.
Time frame: serial pharmacokinetic plasma concentrations were drawn prior to dose administration (0 hour) and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.33, 2.67, 3, 3.33, 3.67, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 14, 18, 24, 36, and 48 hours after drug administration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone With Colchicine | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] Ethinyl Estradiol With Colchicine | 1.24 ng/mL | Standard Deviation 0.41 |
Primary
Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] for Colchicine With Norethindrone/Ethinyl Estradiol
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.
Time frame: Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone With Colchicine | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] for Colchicine With Norethindrone/Ethinyl Estradiol | 18.40 ng/mL | Standard Deviation 4.15 |
Primary
Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] for Ethinyl Estradiol With Placebo
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.
Time frame: Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone With Colchicine | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] for Ethinyl Estradiol With Placebo | 1.29 ng/mL | Standard Deviation 0.4 |
Primary
Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] for Norethindrone With Colchicine
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.
Time frame: Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone With Colchicine | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] for Norethindrone With Colchicine | 175.57 ng-hr/mL | Standard Deviation 60.74 |
Primary
Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] for Norethindrone With Placebo
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.
Time frame: Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone With Colchicine | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] for Norethindrone With Placebo | 178.08 ng/mL | Standard Deviation 51.69 |
Primary
Maximum Plasma Concentration of Colchicine With Norethindrone/Ethinyl Estradiol at Steady State (Cmax, ss)
The maximum or peak concentration that Colchicine with Norethindrone/Ethinyl Estradiol reaches in the plasma at steady state. Steady state refers to the point that constant concentration of drug is achieved subsequent to administration of constant doses of that drug given at constant intervals
Time frame: Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone With Colchicine | Maximum Plasma Concentration of Colchicine With Norethindrone/Ethinyl Estradiol at Steady State (Cmax, ss) | 3.11 ng/mL | Standard Deviation 0.86 |
Primary
Maximum Plasma Concentration of Ethinyl Estradiol With Colchicine at Steady State (Cmax, ss)
The maximum or peak concentration that Ethinyl Estradiol with Colchicine reaches in the plasma at steady state. Steady state refers to the point that constant concentration of drug is achieved subsequent to administration of constant doses of that drug given at constant intervals.
Time frame: Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone With Colchicine | Maximum Plasma Concentration of Ethinyl Estradiol With Colchicine at Steady State (Cmax, ss) | 0.14 ng/mL | Standard Deviation 0.05 |
Primary
Maximum Plasma Concentration of Ethinyl Estradiol With Placebo at Steady State (Cmax, ss)
The maximum or peak concentration that Ethinyl Estradiol with Placebo reaches in the plasma at steady state. Steady state refers to the point that constant concentration of drug is achieved subsequent to administration of constant doses of that drug given at constant intervals.
Time frame: Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone With Colchicine | Maximum Plasma Concentration of Ethinyl Estradiol With Placebo at Steady State (Cmax, ss) | 0.15 ng/mL | Standard Deviation 0.05 |
Primary
Maximum Plasma Concentration of Norethindrone With Colchicine at Steady State (Cmax, ss)
The maximum or peak concentration that Norethindrone with Colchicine reaches in the plasma at steady state. Steady state refers to the point that constant concentration of drug is achieved subsequent to administration of constant doses of that drug given at constant intervals.
Time frame: Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone With Colchicine | Maximum Plasma Concentration of Norethindrone With Colchicine at Steady State (Cmax, ss) | 24.17 ng/mL | Standard Deviation 6.63 |
Primary
Maximum Plasma Concentration of Norethindrone With Placebo at Steady State (Cmax, ss)
The maximum or peak concentration that Norethindrone with Placebo reaches in the plasma at steady state. Steady state refers to the point that constant concentration of drug is achieved subsequent to administration of constant doses of that drug given at constant intervals.
Time frame: Day 21 of each cycle - plasma concentrations were drawn prior to the morning dose (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (prior to pm colchicine/placebo dose), and 24 hours post-dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone With Colchicine | Maximum Plasma Concentration of Norethindrone With Placebo at Steady State (Cmax, ss) | 24.42 ng/mL | Standard Deviation 6.11 |