Healthy
Conditions
Keywords
Bioequivalence, Healthy Subjects
Brief summary
This study will compare the relative bioavailability (rate and extent of absorption) of 20 mg Leflunomide Tablets by TEVA Pharmaceuticals Industries, Ltd. with that of 20 mg ARAVA™ Tablets by Aventis Pharmaceuticals, Inc. following a single oral dose (1 x 20 mg tablet) in healthy adult subjects under fasting conditions.
Detailed description
Criteria for Evaluation: FDA Bioequivalence Criteria Statistical Methods: FDA bioequivalence statistical methods
Interventions
1 x 20 mg, single-dose fasting
DRUGARAVA™ 20 mg Tablets
1 x 20 mg, single-dose 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
* Screening Demographics: All subjects selected for this study will be healthy men or women 18 years of age or older at the time of dosing. The weight range will not exceed ± 20% for height and body frame as per Desirable Weights for Adults - 1983 Metropolitan Height and Weight Table. * Screening procedures: Each subject will complete the screening process within 28 days prior to dosing. Consent documents for both the screening evaluation and HIV antibody determination will be reviewed, discussed, and signed by each potential participant before full implementation of screening procedures. * Screening will include general observations, physical examination, demographics, medical and medication history, an electrocardiogram, sitting blood pressure and heart rate, respiratory rate and temperature. The physical examination will include, but may not be limited to, an evaluation of the cardiovascular, gastrointestinal, respiratory and central nervous systems. * The screening clinical laboratory procedures will include: 1. Hematology: hematocrit, hemoglobin, WBC count with differential, RBC count, platelet count; 2. Clinical Chemistry: serum creatinine, BUN, glucose, AST(GOT), ALT(GPT), albumin, total bilirubin, total protein, and alkaline phosphatase; 3. HIV antibody and hepatitis B surface screens; 4. Urinalysis: by dipstick; full microscopic examination if dipstick positive; and 5. Urine Drug Screen: ethyl alcohol, amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolites, opiates and phencyclidine. 6. Serum Pregnancy Screen (female subjects only) 7. Follicle Stimulating Hormone \[FSH\] (females only to verify postmenopausal status) * If male must be vasectomized (at least 3 months) * If female and: 1. is postmenopausal for at least 1 year; or 2. is surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy).
Exclusion criteria
* Subjects with a recent history of drug or alcohol addiction or abuse. * Subjects with the presence of a clinically significant disorder involving the cardiovascular, respiratory, renal, gastrointestinal, immunologic, hematologic, endocrine, or neurologic system(s) or psychiatric disease (as determined by the clinical investigators). * Subjects whose clinical laboratory test values are outside the accepted reference range and when confirmed on re-examination are deemed to be clinically significant. * Subjects demonstrating a positive hepatitis B surface antigen screen or reactive HIV antibody screen. * Subjects demonstrating a positive drug abuse screen when screened for this study. * Female subjects who are currently breastfeeding. * Female subjects demonstrating a positive pregnancy screen. * Subjects with a history of allergic response(s) to leflunomide or related drugs. * Subjects with a history of clinically significant allergies including drug allergies. * Subjects with a clinically significant illness during the 4 weeks prior to dosing (as determined by the clinical investigators). * Subjects who have taken any drug known to induce or inhibit hepatic drug metabolism in the 30 days prior to dosing. * Subjects who report donating greater than 150 mL of blood within 30 days prior to dosing. All subjects will be advised not to donate blood for four weeks after completing the study. * Subjects who have donated plasma (e.g. plasmapheresis) within 14 days prior to dosing. All subjects will be advised not to donate plasma for four weeks after completing the study. * Subjects who report receiving any investigational drug within 30 days prior to dosing. * Subjects who report taking any prescription medication in the 14 days prior to dosing, with the exception of postmenopausal women on HRT may continue their HRT and topical products without systemic absorption. * Subjects who report an intolerance of direct venipuncture. * Subjects who report consuming an abnormal diet during the 28 days prior to dosing. * Subjects who report taking any product containing leflunomide within 180 days of dosing. * Subjects who report taking any herbal products within 7 days prior to dosing.
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 - 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 | 42 |
| Arava™ Arava™ 20 mg Tablet | 42 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
Baseline characteristics
| Characteristic | Leflunomide | Arava™ | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 38 Participants | 38 Participants | 76 Participants |
| Race/Ethnicity, Customized American Indian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 40 Participants | 40 Participants | 80 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 2 Participants | 3 Participants |
| Region of Enrollment United States | 42 participants | 42 participants | 84 participants |
| Sex: Female, Male Female | 32 Participants | 34 Participants | 66 Participants |
| Sex: Female, Male Male | 10 Participants | 8 Participants | 18 Participants |
Outcome results
Primary
AUC0-72 - Area Under the Concentration-time Curve From Time Zero to 72 Hours Post-dose - 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 - Metabolite A77 1726 | 105806.888 ng*h/mL | Standard Deviation 19068.308 |
| Arava™ | AUC0-72 - Area Under the Concentration-time Curve From Time Zero to 72 Hours Post-dose - Metabolite A77 1726 | 103905.901 ng*h/mL | Standard Deviation 19933.702 |
90% CI: [95.2, 109]
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 | 2109.286 ng/mL | Standard Deviation 407.044 |
| Arava™ | Cmax - Maximum Observed Concentration - Metabolite A77 1726 in Plasma | 1974.000 ng/mL | Standard Deviation 421.291 |
90% CI: [99.6, 116]