Healthy
Conditions
Keywords
Bioequivalence, Healthy Subjects
Brief summary
The objective of this study is to compare the rate and extent of absorption if amlodipine-benzazepril 10 mg-20 mg capsules (test) versus Lotrel® (reference),administered as 1 x 10 mg- 20 mg capsule under fed conditions.
Detailed description
Criteria for Evaluation: FDA Bioequivalence Criteria Statistical Methods: FDA bioequivalence statistical methods
Interventions
1 x 10-20 mg
1 x 10-20 mg
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
* Male of non-child-bearing potential female, non-smoker, 18 years of age and older. * Non-child-bearing potential female subjects is defined as follows: * Post-menopausal state: absence of menses for 12 months prior to drug administration or hysterectomy woth bilateral oophorectomy at least 6 months prior to drug administration. * Surgically sterile: hysterectomy, bilateral oophorectomy, or tubal ligation at least 6 months prior to drug administration. * Capable of consent
Exclusion criteria
* Clinically significant illnesses within 4 weeks prior to the administration of the 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 judges clinically significant. * Positive testing for hepatitis B, hepatitis C, or HIV at screening. * EGC abnormalities (clinically significant) or vital sign abnormalities (systolic blood pressure lower than 100 ot over 140 nnHg, diastolic blood pressure lower than 60 or over 90 mmHg, or heart rate less that 60 or over 100 bpm) at screening. * BMI ≥ 30.0 * History of significant alcohol abuse within six months prior to 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, 360 mL of beer, or 45 mL ot 40% alcohol) or positive alcohol breath test at screening. * History of drug abuse or use of illegal drugs: use of soft drugs (such as marijuana) within 3 months prior to the screening visit or hard drugs( such as cocaine, phencyclidine \[PCP\] and crack) within 1 year prior to the screening visit or positive urine drug screen at screening. * History of allergic reactions to heparin, ramipril, or other ACE inhibitors, or other related drugs. * Use of any drugs known to induce hepatic drug metabolism (examples of inducers: barbiturates, carbamazepine, phenytoin, glucocorticoids, omeprazole; examples of inhibitors: antidepressant (SSRI), cimetidine, diltiazem, macrolides, imidazoles, neuroleptics, verapamil, fluoroquinolones, antihistamines) within 30 days prior to administration of the study medication. * Use of and investigational drug or participation in an investigational study within 30 days prior to administration of the study medication. * Clinically significant history or presence of any clinically significant gastrointestinal pathology (e.g. chronic diarrhea, inflammatory bowel diseases), unresolved gastrointestinal symptoms (e.g. diarrhea, vomiting), liver of kidney disease, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of the drug. * Any clinically significant history or presence of clinically significant neurological, endocrinal, cardiovascular, pulmonary, hematologic, immunologic, psychiatric, or metabolic disease. * Use of prescription medication ( including hormone replacement therapy) within 14 days prior to administration of study medication or over-the-counter products (including natural food supplements, vitamins, garlic as a supplement) within 7 days prior to administration of study medication, except for topical products without systemic absorption. * Difficulty to swallow study medication. Subjects who have used tobacco in any form within the 90 days preceding study drug administration * Any food allergy, intolerance, restriction or special diet that, in the opinion of the Medical Sub-Investigator, could contraindicate the subject's participation in this study. * A depot injection or an implant of any drug within 3 months prior to administration of study medication. * Donation of plasma (500 mL) within 30 days prior to drug administration. Donation or loss of whole blood (excluding the volume of blood that will be drawn during the screening procedures of this study) prior to administration of the study medication as follows: * 50 mL to 300 mL of whole blood within 30 days, * 301 mL to 500 mL of whole blood within 45 days, or * more than 500 mL of whole blood within 56 days prior to drug administration. * Consumption of food or beverages containing grapefruit ( e.g. fresh, canned, or frozen) within 7 days prior to administration of the study medication. * Intolerance to venipunctures * Unable to understand or unwilling to sign the Informed Consent Form. * Clinically significant history of angioedema. Subjects with a clinically significant history or active hypotension. Subjects with a significant history of active neutropenia and/or agranulocytosis. * Breast-feeding subject. * Positive urine pregnancy test at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-t - Benazepril | Blood samples collected over 36 hour period | Bioequivalence based on AUC0-t - Area under the concentration-time curve from time zero to time of last non-zero concentration (per participant) |
| AUC0-t - Amlodipine | Blood samples collected over 168 hour period | Bioequivalence based on AUC0-t - Area under the concentration-time curve from time zero to time of last non-zero concentration (per participant) |
| Cmax - Benazepril | Blood samples collected over 36 hour period | Bioequivalence based on Cmax - Maximum observed concentration |
| AUC0-inf - Benazepril | Blood samples collected over 36 hour period | Bioequivalence based on AUC0-inf - Area under the concentration-time curve from time zero to infinity (extrapolated) |
| Cmax - Amlodipine | Blood samples collected over 168 hour period | Bioequivalence based on Cmax - Maximum observed concentration |
| AUC0-inf - Amlodipine | Blood samples collected over 168 hour period | Bioequivalence based on AUC0-inf - Area under the concentration-time curve from time zero to infinity (extrapolated) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-inf - Benazeprilat | Blood samples collected over 36 hour period | AUC0-inf - Area under the concentration-time curve from time zero to infinity (extrapolated) |
| AUC0-t - Benazeprilat | Blood samples collected over 36 hour period | AUC0-t - Area under the concentration-time curve from time zero to time of last non-zero concentration (per participant) |
| Cmax - Benazeprilat | Blood samples collected over 36 hour period | Cmax - Maximum observed concentration |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Amlodipine Benazepril (Test) First Amlodipine Benazepril 10/20 mg capsule (test)dosed in first period followed by Lotrel® 10/20 mg capsule (reference) dosed in second period | 34 |
| Lotrel® (Reference) First Lotrel® 10/20 mg capsule (reference) dosed in first period followed by Amlodipine Benazepril 10/20 mg capsule (test)dosed in second period | 34 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Second Intervention | Adverse Event | 1 | 1 |
| Washout | Adverse Event | 2 | 0 |
| Washout | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Amlodipine Benazepril (Test) First | Lotrel® (Reference) First | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants | 32 Participants | 64 Participants |
| Race/Ethnicity, Customized American Hispanic | 4 Participants | 6 Participants | 10 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Caucasian | 28 Participants | 27 Participants | 55 Participants |
| Sex: Female, Male Female | 8 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Male | 26 Participants | 28 Participants | 54 Participants |
Outcome results
Primary
AUC0-inf - Amlodipine
Bioequivalence based on AUC0-inf - Area under the concentration-time curve from time zero to infinity (extrapolated)
Time frame: Blood samples collected over 168 hour period
Population: One subject was excluded from all statistical analysis for Amlodipine based on a pre-dose plasma concentration greater than 5% of the Cmax value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Benazepril | AUC0-inf - Amlodipine | 370735.08 pg*h/mL | Standard Deviation 105920.24 |
| Lotrel® | AUC0-inf - Amlodipine | 363080.38 pg*h/mL | Standard Deviation 111778.14 |
90% CI: [99.71, 105.44]
Primary
AUC0-inf - Benazepril
Bioequivalence based on AUC0-inf - Area under the concentration-time curve from time zero to infinity (extrapolated)
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 |
|---|---|---|---|
| Amlodipine Benazepril | AUC0-inf - Benazepril | 201.36 ng*h/mL | Standard Deviation 50.83 |
| Lotrel® | AUC0-inf - Benazepril | 194.76 ng*h/mL | Standard Deviation 47.16 |
90% CI: [100.35, 105.19]
Primary
AUC0-t - Amlodipine
Bioequivalence based on AUC0-t - Area under the concentration-time curve from time zero to time of last non-zero concentration (per participant)
Time frame: Blood samples collected over 168 hour period
Population: One subject was excluded from all statistical analysis for Amlodipine based on a pre-dose plasma concentration greater than 5% of the Cmax value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Benazepril | AUC0-t - Amlodipine | 329314.07 pg*h/mL | Standard Deviation 81902.24 |
| Lotrel® | AUC0-t - Amlodipine | 322615.55 pg*h/mL | Standard Deviation 88414.74 |
90% CI: [99.75, 105.3]
Primary
AUC0-t - Benazepril
Bioequivalence based on AUC0-t - Area under the concentration-time curve from time zero to time of last non-zero concentration (per participant)
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 |
|---|---|---|---|
| Amlodipine Benazepril | AUC0-t - Benazepril | 197.23 ng*h/mL | Standard Deviation 49.99 |
| Lotrel® | AUC0-t - Benazepril | 190.74 ng*h/mL | Standard Deviation 46.58 |
90% CI: [100.3, 105.2]
Primary
Cmax - Amlodipine
Bioequivalence based on Cmax - Maximum observed concentration
Time frame: Blood samples collected over 168 hour period
Population: One subject was excluded from all statistical analysis for Amlodipine based on a pre-dose plasma concentration greater than 5% of the Cmax value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Benazepril | Cmax - Amlodipine | 5621.36 pg/mL | Standard Deviation 1079.24 |
| Lotrel® | Cmax - Amlodipine | 5536.86 pg/mL | Standard Deviation 1183.43 |
90% CI: [98.22, 105.59]
Primary
Cmax - Benazepril
Bioequivalence based on Cmax - Maximum observed concentration
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 |
|---|---|---|---|
| Amlodipine Benazepril | Cmax - Benazepril | 92.13 ng/mL | Standard Deviation 30.76 |
| Lotrel® | Cmax - Benazepril | 101.55 ng/mL | Standard Deviation 39.46 |
90% CI: [84.83, 99.32]
Secondary
AUC0-inf - Benazeprilat
AUC0-inf - Area under the concentration-time curve from time zero to infinity (extrapolated)
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 |
|---|---|---|---|
| Amlodipine Benazepril | AUC0-inf - Benazeprilat | 1645.73 ng*h/mL | Standard Deviation 483.54 |
| Lotrel® | AUC0-inf - Benazeprilat | 1631.10 ng*h/mL | Standard Deviation 458.99 |
90% CI: [98.3, 102.3]
Secondary
AUC0-t - Benazeprilat
AUC0-t - Area under the concentration-time curve from time zero to time of last non-zero concentration (per participant)
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 |
|---|---|---|---|
| Amlodipine Benazepril | AUC0-t - Benazeprilat | 1611.85 ng*h/mL | Standard Deviation 480.27 |
| Lotrel® | AUC0-t - Benazeprilat | 1597.94 ng*h/mL | Standard Deviation 458.32 |
90% CI: [98.25, 102.35]
Secondary
Cmax - Benazeprilat
Cmax - Maximum observed concentration
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 |
|---|---|---|---|
| Amlodipine Benazepril | Cmax - Benazeprilat | 226.79 ng/mL | Standard Deviation 63.9 |
| Lotrel® | Cmax - Benazeprilat | 235.85 ng/mL | Standard Deviation 69.61 |
90% CI: [92.54, 99.27]