Therapeutic Equivalency
Conditions
Brief summary
The purpose of this study is to compare the bioequivalence of a test formulation of primidone tablets to an equivalent oral dose of the commercially available Mysoline®(primidone tablets) in adult subjects under fasting conditions.
Detailed description
The purpose of this study is to compare the bioequivalence of a test formulation of primidone tablets to an equivalent oral dose of the commercially available Mysoline® (primidone tablets) in adult subjects under fasting conditions. Twenty-two healthy, non-smoking, non-obese male and female volunteers at least 18 years of age will be randomly assigned in a crossover fashion to receive each of two primidone dosing regimens in sequence with a 14 day washout period between dosing periods. On the morning of Day 1, after an overnight fast of at least 10 hours, subjects will receive either a single oral dose of the test formulation, primidone (1 x 50 mg tablet) or a single oral dose of the reference formulation, Mysoline® (1 x 50 mg tablet). After a 14 day washout period, on the morning of Day 15 after an overnight fast, subjects will receive the alternate regimen. Blood samples will be drawn from all participants before dosing and for 72 hours post dose at times sufficient to adequately define the pharmacokinetics of primidone. A further goal of this study is to evaluate the safety and tolerability of this regimen in healthy volunteers. Subjects will be monitored throughout the confinement portion of the study for adverse reactions to the study drugs and/or procedures. Blood pressure and heart rate will be obtained prior to dosing and at 3, 4, 6, 24 and 72 hours post-dose. 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
DRUGPrimidone 50 mg Tablet
50 mg tablet administered after an overnight fast of at least 10 hours.
DRUGPrimidone (Mysoline®) 50 mg Tablet
50 mg tablet administered after an overnight fast of at least 10 hours.
Sponsors
Mutual Pharmaceutical Company, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* male or female * at least 18 years of age * weight must be 15% of ideal weight for height and frame * subjects must be in good health and physical condition as determined by medical history * subjects must read and sign consent form
Exclusion criteria
* history of treatment for alcoholism, substance abuse, or drug abuse within the last 24 months * history of malignancy, stroke, diabetes, cardiac, renal or liver disease * history of gastroesophageal reflux disease (GERD), malabsorption syndrome, colon cancer, chronic colitis, including Crohn's disease * history of porphyria, hyperkinesia, respiratory diseases (eg. asthma, emphysema, difficulty breathing, pulmonary obstruction) * females who pregnant or lactating * history of hypersensitivity to primidone, barbiturates, and anticonvulsants * sitting systolic blood pressure below 90mm Hg, or diastolic pressure below 50mm Hg (conditions upon screening which might contraindicate or require that caution be used in the administration of primidone) * heart rate less than 50 beats per minute after a 5 minute rest * treatment with any other investigational drug during the four weeks prior to initial dosing * subjects who have donated blood within four weeks prior to the initial dosing * subjects who smoke or use tobacco products or nicotine products. Three months abstinence is required.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) | 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, 3.5, 4, 4.5, 5, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours after drug administration. | The maximum or peak concentration that the drug reaches in the plasma. |
| Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 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, 3.5, 4, 4.5, 5, 6, 8, 12, 18, 24, 36, 48, 60 and 72 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 Extrapolated to Infinity [AUC(0-∞)] | 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, 3.5, 4, 4.5, 5, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours after drug 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Primidone 50 mg Tablets and Mysoline® 50 mg Tablets All subjects received each of the two study regimens in a randomly assigned sequence of dosing periods. On the mornings of Day 1 and Day 15, each subject received one tablet of either primidone 50 mg or Mysoline® 50 mg following an overnight fast of at least 10 hours. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout Period of 14 Days | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Primidone 50 mg Tablets and Mysoline® 50 mg Tablets |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants |
| Age Continuous | 31.76 years STANDARD_DEVIATION 12.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 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 | 3 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 22 | 3 / 21 |
| serious Total, serious adverse events | 0 / 22 | 0 / 21 |
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.
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, 3.5, 4, 4.5, 5, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours after drug administration.
Population: Plasma concentration data for 21 of 22 participants were used in the statistical analysis. One subject dropped from the study before Period II dosing due to an adverse event.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Primidone 50 mg Tablets | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 31,162.82 ng-hr/mL |
| Mysoline® 50 mg Tablets | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 30,583.92 ng-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.
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, 3.5, 4, 4.5, 5, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours after drug administration.
Population: Plasma concentration data for 21 of 22 participants were used in the statistical analysis. One subject dropped from the study before Period II dosing due to an adverse event.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Primidone 50 mg Tablets | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 27,893.57 ng-hr/mL |
| Mysoline® 50 mg Tablets | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 27,519.67 ng-hr/mL |
Primary
Maximum Plasma Concentration (Cmax)
The maximum or peak concentration that the drug reaches in the plasma.
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, 3.5, 4, 4.5, 5, 6, 8, 12, 18, 24, 36, 48, 60 and 72 hours after drug administration.
Population: Plasma concentration data for 21 of 22 participants were used in the statistical analysis. One subject dropped from the study before Period II dosing due to an adverse event.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Primidone 50 mg Tablets | Maximum Plasma Concentration (Cmax) | 1,165.92 ng/mL | Standard Deviation 216.64 |
| Mysoline® 50 mg Tablets | Maximum Plasma Concentration (Cmax) | 1,202.28 ng/mL | Standard Deviation 273.28 |