Healthy
Conditions
Keywords
Bioequivalence, Healthy Subjects
Brief summary
The objective of this study is to compare the rate and extent of absorption of Glyburide/Metformin 5 mg/500 mg film-coated tablets (test) versus Glucovance® (reference) administered as 1 x 5 mg/500 mg film-coated tablet under fed conditions.
Detailed description
Criteria for Evaluation: FDA Bioequivalence Criteria Statistical Methods: FDA bioequivalence statistical methods
Interventions
1 x 5 mg/500 mg, single-dose fed
1 x 5 mg/500 mg, single-dose fed
Sponsors
Teva Pharmaceuticals USA
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Subjects will be females and/or males, non-smokers, 18 years of age and older.
Exclusion criteria
* Clinically significant illnesses within 4 weeks of the administration of study medication. * Clinically significant surgery within 4 weeks prior to the administration of the study medication. * Any clinically significant abnormality found during medical screening. * Any reason which, in the opinion of the medical sub-investigator, would prevent the subject from participating in the study. * Abnormal laboratory tests judged clinically significant. * Positive urine drug screen at screening. * Positive testing for hepatitis B, hepatitis C or HIV at screening. * Subjects with BMI less than or equal to 30.0. * History of significant alcohol abuse within six months of the screening visit or any indication of the regular use of more than fourteen units of alcohol per week (1 Unit = 150 mL of wine or 360 mL of beer or 45 mL of alcohol 40%). * History of drug abuse or use of illegal drugs: use of soft drugs (such as marijuana) within 3 months of the screening visit or hard drugs (such as cocaine, phencyclidine (PCP) and crack) within 1 year of the screening visit. * History of allergic reactions to glyburide or to metformin or other related drugs (e.g. chlorpropamide, gliclazide, tolbutamide, furosemide, sulfamethoxazole, sulfadiazine and sulfisoxazole). * Use of any drugs known to induce or inhibit hepatic drug metabolism (examples of inducers: barbiturates, carbamazepine, phenytoin, glucocorticoids, rifampin/rifabutin; examples of inhibitors: antidepressants, cimetidine, diltiazem, erythromycin, ketoconazole, MAO inhibitors, neuroleptics, verapamil, quinidine) within 30 days prior to administration of the study medication. * Use of an investigational drug or participation in an investigational study within 30 days prior to administration of the study medication. * History or presence of any clinically significant gastrointestinal pathology (e.g. chronic diarrhea, inflammatory bowel diseases), unresolved gastrointestinal symptoms (e.g. diarrhea, vomiting), liver or kidney disease or other conditions known to interfere with the absorption, distribution, metabolism or excretion of the drug. * Any history or presence of clinically significant neurological, endocrinal, cardiovascular, pulmonary, hematologic, immunologic, psychiatric or metabolic disease. * Use of prescription medication within 14 days prior to administration of study medication or over-the-counter products (including natural food supplements, vitamins, garlic as supplement) within 7 days prior to administration of study medication except for topical products without systemic absorption. * Positive alcohol breath test at screening. subjects who have used tobacco in any form within the 90 days preceding study drug administration. * Intolerance to venipuncture. * Any food allergy, intolerance, restriction, or special diet that, in the opinion of the medical sub-investigator, contraindicates the subject's participation in this study. * Subjects who have had a depot injection or an implant of any drug 3 months prior to administration of study medication. * Donation of plasma (500 mL) within 7 days. Donation or loss of whole blood prior to administration of the study medication as follows: less than 300 mL of whole blood within 30 days or; 300 mL to 500 mL of whole blood within 45 days or; more than 500 mL of whole blood within 56 days. * Subjects with a clinically significant history of tuberculosis, epilepsy, asthma, diabetes, psychosis or glaucoma will not be eligible for this study. * History of metabolic acidosis, congestive heart failure and myocardial infarction. * Breast-feeding subjects. * Positive urine pregnancy test at screening (performed on all females). * Female subjects of childbearing potential who have had unprotected sexual intercourse with any non-steril male partner (i.e. male who has not been sterilized by vasectomy for at least 6 months) within 14 days prior to study drug administration. The acceptable methods of contraception are: 1. Condom + spermicide 2. Diaphragm + spermicide 3. Intrauterine contraceptive device (placed at least 4 weeks prior to study drug administration)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax (Maximum Observed Concentration) - Glyburide | Blood samples collected over 36 hour period | Bioequivalence based on Cmax |
| AUC0-inf [Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated)] - Glyburide | Blood samples collected over 36 hour period | Bioequivalence based on AUC0-inf |
| AUC0-t [Area Under the Concentration-time Curve From Time Zero to Time of Last Non-zero Concentration (Per Participant)] - Glyburide | Blood samples collected over 36 hour period | Bioequivalence based on AUC0-t |
| Cmax (Maximum Observed Concentration) - Metformin | Blood samples collected over 36 hour period | Bioequivalence based on Cmax |
| AUC0-inf [Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated)] - Metformin | Blood samples collected over 36 hour period | Bioequivalence based on AUC0-inf |
| AUC0-t [Area Under the Concentration-time Curve From Time Zero to Time of Last Non-zero Concentration (Per Participant)] - Metformin | Blood samples collected over 36 hour period | Bioequivalence based on AUC0-t |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Glyburide Metformin (Test) First Glyburide Metformin 5/500 Film-Coated Tablet (test) dosed in first period followed by Glucovance® 5/500 mg Tablet (reference) dosed in second period | 30 |
| Glucovance® (Reference) First Glucovance® 5/500 mg Tablet (reference) dosed in first period followed by Glyburide Metformin 5/500 mg Film-Coated Tablet (test) dosed in second period | 30 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Adverse Event | 0 | 1 |
| Washout | Protocol Violation | 0 | 2 |
| Washout | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Glyburide Metformin (Test) First | Glucovance® (Reference) First | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 28 Participants | 54 Participants |
| Race/Ethnicity, Customized American Hispanic | 4 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Caucasian | 24 Participants | 27 Participants | 51 Participants |
| Region of Enrollment Canada | 30 participants | 30 participants | 60 participants |
| Sex: Female, Male Female | 10 Participants | 10 Participants | 20 Participants |
| Sex: Female, Male Male | 20 Participants | 20 Participants | 40 Participants |
Outcome results
Primary
AUC0-inf [Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated)] - Glyburide
Bioequivalence based on AUC0-inf
Time frame: Blood samples collected over 36 hour period
Population: Data from all subjects who completed the study were included in the statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glyburide Metformin | AUC0-inf [Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated)] - Glyburide | 970.22 ng*h/mL | Standard Deviation 328.93 |
| Glucovance® | AUC0-inf [Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated)] - Glyburide | 977.28 ng*h/mL | Standard Deviation 402.74 |
90% CI: [97.59, 103.76]
Primary
AUC0-inf [Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated)] - Metformin
Bioequivalence based on AUC0-inf
Time frame: Blood samples collected over 36 hour period
Population: Data from all subjects who completed the study were included in the statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glyburide Metformin | AUC0-inf [Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated)] - Metformin | 6308.12 ng*h/mL | Standard Deviation 1662.69 |
| Glucovance® | AUC0-inf [Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated)] - Metformin | 6552.79 ng*h/mL | Standard Deviation 1833.42 |
90% CI: [93.85, 99.32]
Primary
AUC0-t [Area Under the Concentration-time Curve From Time Zero to Time of Last Non-zero Concentration (Per Participant)] - Glyburide
Bioequivalence based on AUC0-t
Time frame: Blood samples collected over 36 hour period
Population: Data from all subjects who completed the study were included in the statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glyburide Metformin | AUC0-t [Area Under the Concentration-time Curve From Time Zero to Time of Last Non-zero Concentration (Per Participant)] - Glyburide | 942.94 ng*h/mL | Standard Deviation 316.17 |
| Glucovance® | AUC0-t [Area Under the Concentration-time Curve From Time Zero to Time of Last Non-zero Concentration (Per Participant)] - Glyburide | 943.45 ng*h/mL | Standard Deviation 388.26 |
90% CI: [98.32, 104.48]
Primary
AUC0-t [Area Under the Concentration-time Curve From Time Zero to Time of Last Non-zero Concentration (Per Participant)] - Metformin
Bioequivalence based on AUC0-t
Time frame: Blood samples collected over 36 hour period
Population: Data from all subjects who completed the study were included in the statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glyburide Metformin | AUC0-t [Area Under the Concentration-time Curve From Time Zero to Time of Last Non-zero Concentration (Per Participant)] - Metformin | 6203.57 ng*h/mL | Standard Deviation 1656.57 |
| Glucovance® | AUC0-t [Area Under the Concentration-time Curve From Time Zero to Time of Last Non-zero Concentration (Per Participant)] - Metformin | 6448.34 ng*h/mL | Standard Deviation 1814.06 |
90% CI: [93.71, 99.25]
Primary
Cmax (Maximum Observed Concentration) - Glyburide
Bioequivalence based on Cmax
Time frame: Blood samples collected over 36 hour period
Population: Data from all subjects who completed the study were included in the statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glyburide Metformin | Cmax (Maximum Observed Concentration) - Glyburide | 190.17 ng/mL | Standard Deviation 68.08 |
| Glucovance® | Cmax (Maximum Observed Concentration) - Glyburide | 166.48 ng/mL | Standard Deviation 59.87 |
90% CI: [107.26, 121.27]
Primary
Cmax (Maximum Observed Concentration) - Metformin
Bioequivalence based on Cmax
Time frame: Blood samples collected over 36 hour period
Population: Data from all subjects who completed the study were included in the statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glyburide Metformin | Cmax (Maximum Observed Concentration) - Metformin | 755.10 ng/mL | Standard Deviation 195.97 |
| Glucovance® | Cmax (Maximum Observed Concentration) - Metformin | 766.30 ng/mL | Standard Deviation 210.22 |
90% CI: [94.31, 104.02]