Healthy
Conditions
Keywords
Bioequivalence, Healthy
Brief summary
The object of this study is to compare the rate and extent of absorption of an investigational formulation of buprenorphine 8 mg sublingual tablets manufactured by Barr Laboratories, Inc. to an equivalent oral dose of the commercially available reference product, Subutex® manufactured by Reckitt Benckiser, following and overnight fast of at least 10 hours.
Detailed description
Criteria for Evaluation: FDA Bioequivalence Criteria Statistical Methods: FDA Bioequivalence Statistical Methods
Interventions
DRUGBuprenorphine
8 mg Sublingual Tablets
Sponsors
Teva Pharmaceuticals USA
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Subject must be a male or non-pregnant, non-breastfeeding female. * Subject must be between 18 and 45 years of age (inclusive). * Subject's Body Mass Index (BMI) must be between 18 and 30 (inclusive), and subject must weigh a minimum of 50 kg (110 lbs). * Female subjects must agree to utilize one of the following forms of contraception from screening through 4 weeks after completion of the study. Approved forms of contraception are abstinence, double barrier, IUD in place at least 30 days prior to study drug administration, vasectomized partner, surgically sterile for at least 6 months, or at least 2 years postmenopausal. * Subject must voluntarily consent to participate in this study and provide their written informed consent prior to completion of any study-specific procedures. * Subject is willing and able to remain in the study unit for the entire duration of the confinement period and return for all scheduled outpatient visits.
Exclusion criteria
* History or presence of any clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease or any other condition that, in the opinion of the investigator, would jeopardize the safety of the subject or the validity of the study results. * History or presence of pancreatitis, bowel obstruction, glaucoma, enlargement of the prostate, adrenal disease, hyperthyroidism, or gallbladder disease. Subjects with a history of cholecystectomy for the treatment of gallbladder disease will be excluded. * Females taking any oral contraceptives including estrogen and progestin combined pills, progestin-only pills, patch, or vaginal ring within 28 days prior to the first dose of study medication; using injectable contraceptives within 6 months of first dose; or who have ever had progestational hormone implants. * Females taking hormone replacement therapy within 60 days prior to the first dose of study medication. * Has a clinically significant abnormal finding on the physical exam, medical history, ECG, or clinical laboratory results at screening. * History or presence of allergic or adverse response to buprenorphine, naltrexone, or any comparable or similar product. * Has been on a significantly abnormal diet during the 4 weeks preceding the first dose of study medication. * Has donated blood or plasma within 30 days prior to the first dose of study medication. * Has participated in another clinical trial within 30 days prior to the first dose of study medication. * Has used any over-the-counter (OTC) medication, including cough and cold preparations, vitamins, and herbal supplements, within 7 days prior to the first dose of study medication. * Has used any prescription medication within 14 days prior to the first dose of study medication. * Has consumed beverages or food containing alcohol, caffeine/xanthine, or poppy seeds from 48 hours prior to the first dose of study medication or has consumed beverages or foods containing grapefruit from 14 days prior to the first dose of study medication. * Has been treated with any known enzyme-altering drugs, such as barbiturates, phenothiazines, cimetidine, carbamazepine, etc., within 30 days prior to the first dose of study medication. * Has smoked or used tobacco products within 60 days prior to the first dose of study medication. * Has a history of treatment for substance abuse (including alcohol) in the past 5 years. * Is a female with a positive pregnancy test result. * Has any piercing of the tongue or has a lip piercing within 30 days prior to the first dose of study medication. * Has a positive urine screen for drugs of abuse. * Has a positive urine alcohol test or ethanol breath test. * Has a positive test for or has been treated for hepatitis B, hepatitis C, or HIV.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of Buprenorphine. | Blood samples collected over a 144 hour period. | Bioequivalence based on Buprenorphine Cmax (maximum observed concentration of drug substance in plasma). |
| AUC0-t for Buprenorphine. | Blood samples collected over a 144 hour period. | Bioequivalence based on Buprenorphine AUC0-t (area under the concentration-time curve from time zero to time of last measurable concentration). |
| AUC0-inf for Buprenorphine. | Blood samples collected over a 144 hour period. | Bioequivalence based on Buprenorphine AUC0-inf (area under the concentration-time curve from time zero to infinity). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax for Norbuprenorphine. | Blood samples collected over a 144 hour period. | Informational comparison of Cmax (maximum observed concentration of drug substance in plasma) values for the metabolite Norbuprenorphine. |
| AUC0-t for Norbuprenorphine. | Blood samples collected over a 144 hour period. | Informational comparison of AUC0-t (area under the concentration-time curve from time zero to time of last measurable concentration) values for the metabolite Norbuprenorphine. |
| AUC0-inf for Norbuprenorphine. | Blood samples collected over a 144 hour period. | Informational comparison of AUC0-inf (area under the concentration-time curve from time zero to infinity) values for the metabolite Norbuprenorphine. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Buprenorphine (Test) First 8 mg Buprenorphine Sublingual Tablets test product dosed in first period followed by 8 mg Subutex® Sublingual Tablets reference product dosed in the second period. | 20 |
| Subutex® (Reference) First 8 mg Subutex® Sublingual Tablets reference product dosed in first period followed by 8 mg Buprenorphine Sublingual Tablets test product dosed in the second period. | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Emesis Within 4 hrs of Administration | 4 | 2 |
| Second Intervention | Emesis Within 4 hrs of Administration | 0 | 1 |
Baseline characteristics
| Characteristic | Buprenorphine (Test) First | Subutex® (Reference) 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 | 20 Participants | 20 Participants | 40 Participants |
| Race/Ethnicity, Customized American Indian | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black | 3 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized Caucasian | 9 participants | 12 participants | 21 participants |
| Race/Ethnicity, Customized Hispanic | 7 participants | 5 participants | 12 participants |
| Region of Enrollment United States | 20 participants | 20 participants | 40 participants |
| Sex: Female, Male Female | 9 Participants | 6 Participants | 15 Participants |
| Sex: Female, Male Male | 11 Participants | 14 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 40 | 13 / 40 |
| serious Total, serious adverse events | 0 / 40 | 0 / 40 |
Outcome results
Primary
AUC0-inf for Buprenorphine.
Bioequivalence based on Buprenorphine AUC0-inf (area under the concentration-time curve from time zero to infinity).
Time frame: Blood samples collected over a 144 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buprenorphine (Test) | AUC0-inf for Buprenorphine. | 37.19 ng*h/mL | Standard Deviation 13.39 |
| Subutex® (Reference) | AUC0-inf for Buprenorphine. | 35.73 ng*h/mL | Standard Deviation 13.93 |
90% CI: [97.18, 111.24]
Primary
AUC0-t for Buprenorphine.
Bioequivalence based on Buprenorphine AUC0-t (area under the concentration-time curve from time zero to time of last measurable concentration).
Time frame: Blood samples collected over a 144 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buprenorphine (Test) | AUC0-t for Buprenorphine. | 35.12 ng*h/mL | Standard Deviation 12.55 |
| Subutex® (Reference) | AUC0-t for Buprenorphine. | 32.92 ng*h/mL | Standard Deviation 12.04 |
90% CI: [99.74, 112.45]
Primary
Cmax of Buprenorphine.
Bioequivalence based on Buprenorphine Cmax (maximum observed concentration of drug substance in plasma).
Time frame: Blood samples collected over a 144 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buprenorphine (Test) | Cmax of Buprenorphine. | 4.40 ng/mL | Standard Deviation 2.16 |
| Subutex® (Reference) | Cmax of Buprenorphine. | 3.88 ng/mL | Standard Deviation 1.82 |
90% CI: [101.67, 120.07]
Secondary
AUC0-inf for Norbuprenorphine.
Informational comparison of AUC0-inf (area under the concentration-time curve from time zero to infinity) values for the metabolite Norbuprenorphine.
Time frame: Blood samples collected over a 144 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buprenorphine (Test) | AUC0-inf for Norbuprenorphine. | 50.77 ng*h/mL | Standard Deviation 28.99 |
| Subutex® (Reference) | AUC0-inf for Norbuprenorphine. | 51.04 ng*h/mL | Standard Deviation 22.12 |
90% CI: [86.56, 104.39]
Secondary
AUC0-t for Norbuprenorphine.
Informational comparison of AUC0-t (area under the concentration-time curve from time zero to time of last measurable concentration) values for the metabolite Norbuprenorphine.
Time frame: Blood samples collected over a 144 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buprenorphine (Test) | AUC0-t for Norbuprenorphine. | 45.34 ng*h/mL | Standard Deviation 18.72 |
| Subutex® (Reference) | AUC0-t for Norbuprenorphine. | 47.58 ng*h/mL | Standard Deviation 17.91 |
90% CI: [87.44, 101.46]
Secondary
Cmax for Norbuprenorphine.
Informational comparison of Cmax (maximum observed concentration of drug substance in plasma) values for the metabolite Norbuprenorphine.
Time frame: Blood samples collected over a 144 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Buprenorphine (Test) | Cmax for Norbuprenorphine. | 1.58 ng/mL | Standard Deviation 0.719 |
| Subutex® (Reference) | Cmax for Norbuprenorphine. | 1.64 ng/mL | Standard Deviation 0.643 |
90% CI: [85.37, 101.93]