Healthy
Conditions
Keywords
Bioequivalence, Healthy Subjects
Brief summary
This study will compare the relative bioavailability of 500 mg Divalproex Sodium Delayed-Release Tablets with that of 500 mg Depakote® Tablets following a single oral dose (1 x 500 mg tablets)in healthy subjects under fasting conditions.
Detailed description
Criteria for Evaluation: FDA Bioequivalence Criteria Statistical Methods: FDA bioequivalence statistical methods
Interventions
DRUGdivalproex sodium
delayed-release 500 mg tablet
DRUGDepakote®
delayed-release 500 mg tablet
Sponsors
Teva Pharmaceuticals USA
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Screening Demographics: All subjects selected for this study will be healthy men or women 18-65 years of age, inclusive, at the time of dosing. The subject's body mass index (BMI) should be less than or equal to 30. * Screening Procedures: Each subject will complete the screening process within 28 days prior to period I 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: * HEMATOLOGY: hematocrit, hemoglobin, WBC count with differential, RBC count, platelet count * CLINICAL CHEMISTRY: serum creatinine, BUN, glucose, AST(GOT), ALT(GPT), albumin, total bilirubin, total protein, and alkaline phosphatase * HIV antibody, hepatitis B surface antigen, hepatitis C antibody screens * URINALYSIS: by dipstick; full microscopic examination if dipstick positive * URINE DRUG SCREEN: ethyl alcohol, amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolites, opiates and phencyclidine * SERUM PREGNANCY SCREEN (female subjects only) * FOLLICLE STIMULATING HORMONE (FSH; female subjects only): verify postmenopausal status If female and: * Is postmenopausal for at least 1 year with postmenopausal status defined as: \> 60 years of age and amenorrheic for at least one year; if 60 years of age or younger, must also have a serum FSH level \> 30 IU/L; or * Is surgically sterile for at least 6 months (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, a positive hepatitis C antibody screen, or a reactive HIV antibody screen. * Subjects demonstrating a positive drug abuse screen when screened for this study. * Female subjects demonstrating a positive pregnancy screen. * Female subjects who are currently breastfeeding. * Subjects with a history of allergic response(s) to divalproex sodium 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 Period I dosing (as determined by the clinical investigators). * Subjects who currently or report using tobacco products within 90 days of Period I dose administration. * Subjects who have taken any drug known to induce or inhibit hepatic drug metabolism in the 28 days prior to Period I dosing. * Subjects who report donating greater than 150 mL of blood within 28 days prior to Period I 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 Period I 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 28 days prior to Period I dosing. * Subjects who report taking any systemic prescription medication in the 14 days prior to Period I dosing. * Subjects who report an intolerance of direct venipuncture. * Subjects who report consuming an abnormal diet during the 28 days prior to Period I dosing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax (Maximum Observed Concentration) | Blood samples collected over a 72 hour period. | Bioequivalence based on Cmax. |
| AUC0-t (Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Blood samples collected over a 72 hour period. | Bioequivalence based on AUC0-t. |
| AUC0-inf (Area Under the Concentration-time Curve From Time Zero to Infinity) | Blood samples collected over a 72 hour period. | Bioequivalence based on AUC0-inf. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Divalproex Sodium First 500 mg Divalproex Sodium Delayed Release Tablets test product dosed in first period followed by 500 mg Depakote® Delayed Release Tablets reference product dosed in the second period. | 12 |
| Depakote® First 500 mg Depakote® Delayed Release Tablets reference product dosed in first period followed by 500 mg Divalproex Sodium Delayed Release Tablets test product dosed in the second period. | 12 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Second Intervention | Physician Decision | 0 | 2 |
Baseline characteristics
| Characteristic | Divalproex Sodium First | Depakote® First | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 12 Participants | 24 Participants |
| Race/Ethnicity, Customized Black | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Hispanic | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 11 participants | 10 participants | 21 participants |
| Region of Enrollment United States | 12 participants | 12 participants | 24 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 12 Participants | 11 Participants | 23 Participants |
Outcome results
Primary
AUC0-inf (Area Under the Concentration-time Curve From Time Zero to Infinity)
Bioequivalence based on AUC0-inf.
Time frame: Blood samples collected over a 72 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Divalproex Sodium | AUC0-inf (Area Under the Concentration-time Curve From Time Zero to Infinity) | 982.25 µg*h/mL | Standard Deviation 223.64 |
| Depakote® | AUC0-inf (Area Under the Concentration-time Curve From Time Zero to Infinity) | 978.75 µg*h/mL | Standard Deviation 235.36 |
90% CI: [97.35, 103.46]
Primary
AUC0-t (Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Bioequivalence based on AUC0-t.
Time frame: Blood samples collected over a 72 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Divalproex Sodium | AUC0-t (Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | 905.18 µg*h/mL | Standard Deviation 195.96 |
| Depakote® | AUC0-t (Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | 898.24 µg*h/mL | Standard Deviation 205.74 |
90% CI: [97.07, 104.24]
Primary
Cmax (Maximum Observed Concentration)
Bioequivalence based on Cmax.
Time frame: Blood samples collected over a 72 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Divalproex Sodium | Cmax (Maximum Observed Concentration) | 53.89 µg/mL | Standard Deviation 5.15 |
| Depakote® | Cmax (Maximum Observed Concentration) | 55.19 µg/mL | Standard Deviation 5.65 |
90% CI: [93.68, 101.18]