Healthy
Conditions
Keywords
Bioequivalence, Healthy Subjects
Brief summary
The objective of this study is to compare the relative bioavailability of leflunomide 20 mg tablets (manufactured by TEVA Pharmaceutical Industries, Ltd. and distributed by TEVA Pharmaceuticals USA) with that of ARAVA 20 mg tablets (Aventis) in healthy, adult, non-smoking subjects \[females (who are unable to become pregnant) and vasectomized males\] under non-fasting conditions.
Detailed description
Criteria for Evaluation: FDA Bioequivalence Criteria Statistical Methods: FDA bioequivalence statistical methods
Interventions
DRUGARAVA® 20 mg tablets
1 x 20 mg, single-dose non-fasting
1 x 20 mg, single-dose non-fasting
Sponsors
Teva Pharmaceuticals USA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* All subjects selected for this study will be non-smokers at least 18 years of age. Females must be physically unable to become pregnant. Males must be vasectomized. Weight of the subjects shall not be more than 20% ± from normal for height and body frame (Metropolitan Life, 1993, Height, Weight, Body Chart). * Each subject shall be given a general physical examination within 21 days of initiation of the study. Such examination includes, but is not limited to, blood pressure, general observations, and history. * Each female subject will be given a serum pregnancy test as part of the pre-study screening process. * Adequate blood and urine samples should be obtained within 21 days before beginning of the first period and at th eend of the trial for clinical laboratory measurements. * Clinical laboratory measurements will include the following: 1. Hematology: hematocrit, hemoglobin, red blood cell count, platelets, white blood cell count (with differential). 2. Clinical chemistry: creatinine, BUN, glucose, SGOT/AST, SGPT/ALT, bilirubin, and alkaline phosphatase. 3. Urine Analysis: pH, specific gravity, protein, glucose, ketones, bilirubin, occult blood, and cells. 4. HIV Screen: pre-study only. 5. Hepatitis-B, C Screen: pre-study only. 6. Drugs of Abuse Screen: pre-study and at check-in before dosing. * Subjects will be selected if all above are normal.
Exclusion criteria
* Subjects with a history of chronic alcohol consumption (during past 2 years), drug addiction, or recent serious gastrointestinal, renal, hepatic or cardiovascular disease, tuberculosis, epilepsy, asthma, diabetes, psychosis or glaucoma will not be eligible for this study. * Subjects whose clinical laboratory test values are greater than 20% outside the normal range may be retested. if the clinical values are outside the range on retesting, the subject will not be eligible to participate in the study unless the clinical investigator deems the result to not be significant. * Subjects who have a history of allergic responses to the class of drug being tested should be excluded from the study. Subjects who have a history of allergic responses to cholestyramine should be excluded from the study. * All subjects will have urine samples assayed for the presence of drugs of abuse as part of the clinical laboratory screening procedures and at check-in before dosing. Subjects found to have urine concentrations of any of the tested drugs will not be allowed to participate. * Subjects should not have donated blood and/or plasma for at least 30 days prior to the first dosing of the study. * Subjects who have taken any investigational drug within 30 days prior to the first dosing of the study will not be allowed to participate. * Female subjects who are pregnant or who are able (women with child bearing potential) to become pregnant during the study will not be allowed to participate. * All female subjects will be screened for pregnancy at check-in. Subjects with positive or inconclusive results will be withdrawn from the study. * Male subjects who are physically able to father a child will not be allowed to participate. Male subjects must be vasectomized (at least 3 months) with medical verification. * Subjects who smoke or use tobacco in any form will not be eligible to participate in the study. Three months abstinence is required. * Subjects who are unable to tolerate multiple venipuncture will be excluded. * Subjects who have taken any product containing leflunomide within 180 days of dosing will not be allowed to participate in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax - Maximum Observed Concentration - Metabolite A77 1726 in Plasma | Blood samples collected over 72 hour period | Bioequivalence based on Cmax |
| AUC0-72 - Area Under the Concentration-time Curve From Time Zero to 72 Hours Post-dose (Per Participant) - Metabolite A77 1726 | Blood samples collected over 72 hour period | Bioequivalence based on AUC0-72 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Leflunomide Leflunomide 20 mg Tablet | 20 |
| Arava® Arava® 20 mg Tablet | 17 |
| Total | 37 |
Baseline characteristics
| Characteristic | Leflunomide | Arava® | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 16 Participants | 35 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 19 Participants | 17 Participants | 36 Participants |
| Region of Enrollment United States | 20 participants | 17 participants | 37 participants |
| Sex: Female, Male Female | 13 Participants | 10 Participants | 23 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 14 Participants |
Outcome results
Primary
AUC0-72 - Area Under the Concentration-time Curve From Time Zero to 72 Hours Post-dose (Per Participant) - Metabolite A77 1726
Bioequivalence based on AUC0-72
Time frame: Blood samples collected over 72 hour period
Population: Data from all subjects who completed the study were included in the statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Leflunomide | AUC0-72 - Area Under the Concentration-time Curve From Time Zero to 72 Hours Post-dose (Per Participant) - Metabolite A77 1726 | 132584.730 ng*h/mL | Standard Deviation 18639.707 |
| Arava® | AUC0-72 - Area Under the Concentration-time Curve From Time Zero to 72 Hours Post-dose (Per Participant) - Metabolite A77 1726 | 123335.784 ng*h/mL | Standard Deviation 13732.783 |
90% CI: [100, 115]
Primary
Cmax - Maximum Observed Concentration - Metabolite A77 1726 in Plasma
Bioequivalence based on Cmax
Time frame: Blood samples collected over 72 hour period
Population: Data from all subjects who completed the study were included in the statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Leflunomide | Cmax - Maximum Observed Concentration - Metabolite A77 1726 in Plasma | 2488.000 ng/mL | Standard Deviation 385.181 |
| Arava® | Cmax - Maximum Observed Concentration - Metabolite A77 1726 in Plasma | 2345.294 ng/mL | Standard Deviation 266.156 |
90% CI: [98, 114]