Healthy
Conditions
Keywords
Bioequivalence, Healthy Subjects
Brief summary
The objective of this study is to compare the rate and extent of absorption of Ramipril 10 mg capsule (test) versus Altace® (reference) administered as the content of 1 x 10 mg capsule mixed with applesauce under fasting conditions.
Detailed description
Criteria for Evaluation: FDA Bioequivalence Criteria Statistical Methods: FDA bioequivalence statistical methods
Interventions
1 x 10 mg
1 x 10 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 or non-childbearing potential female, light smoker of non-smoker 18 years of age and older. * Capable of consent * Non-childbearing potential female subject is defined as follows: * Post-menopausal state: absence of menses for 12 months prior to drug administration or hysterectomy with bilateral oophorectomy at least 6 months prior to drug administration, or * Surgically sterile: hysterectomy, bilateral oophorectomy, or tubule ligation at least 6 months prior to drud administration.
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 judged clinically significant, specifically BUN, serum creatinine and hyperkalemia. * Positive testing for hepatitis B, hepatitis C, or HIV at screening. * EcG abnormalities (clinically significant) or vital sign abnormalities (systolic blood pressure lower than 100 or over 140 mmHg, diastolic blood pressure lower than 60 or over 90 mmHg, or heart rate less than 50 or over 100 bpm) or change in the systolic blood pressure of 20 mmHg, or diastolic blood pressure of 10mmHg when passing from supine (after at least 5 minutes) to standing position ( after 1-3 minutes), at screening. * BMI ≥30.0kg/m2. * History of significant alcohol abuse within 6 months prior to the screening visit of any indication of the regular use of more than 14 units of alcohol per week ( 1 Unit= 150 mL of wine, 360 mL of beer, or 45 mL of 40% hard 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 of hard drugs (such as cocaine, phencyclidine \[PCP\] and crack) within 1 year prior to the screening visit of 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, phenytoine, 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 hte 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. * Smoking more than 10 cigarettes per day. * 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. * Intolerance to venipunctures * Clinically significant history of renal, hepatic or cardiovascular disease, tuberculosis, epilepsy, asthma, diabetes, psychosis or glaucoma will nor be eligible for this study. * Unable to understand or unwilling to sign the Informed Consent Form. * Clinically significant history of angioedema. * History of known presence of volume-depletion (diuretics, dialysis, gastrointestinal disease) or hypotension. * History of collagen-vascular disease and/or renal disease. * History of ischemic heart disease, congestive heart failure, or cerebrovascular disease. * Breast-feeding subject. * Positive urine pregnancy test at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax (Maximum Observed Concentration of Drug Substance in Plasma)for Ramipril. | 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) for Ramipril. | 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) for Ramipril. | Blood samples collected over a 72 hour period. | Bioequivalence based on AUC0-inf. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax (Maximum Observed Concentration of Drug Substance in Plasma)for Ramiprilat. | Blood samples collected over a 72 hour period. | Informational comparison of Cmax values for the metabolite Ramiprilat. |
| AUC0-72 (Area Under the Concentration-time Curve From Time Zero to Time of 72 Hours) for Ramiprilat. | Blood samples collected over a 72 hour period. | Informational comparison of AUc0-72 values for the metabolite Ramiprilat. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Test (Ramipril) First 10 mg Ramipril Capsules test product dosed in first period followed by 10 mg Altace® Capsules reference product dosed in the second period. | 20 |
| Reference (Altace®) First 10 mg Altace® Capsules reference product dosed in first period followed by 10 mg Ramipril Capsules test product dosed in the second period. | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Withdrawal by Subject | 0 | 1 |
| Second Intervention | Physician Decision | 0 | 1 |
| Washout of 42 Days | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Test (Ramipril) First | Reference (Altace®) First | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 20 Participants | 39 Participants |
| Race/Ethnicity, Customized Asian | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Hispanic | 2 participants | 4 participants | 6 participants |
| Race/Ethnicity, Customized White | 18 participants | 13 participants | 31 participants |
| Region of Enrollment Canada | 20 participants | 20 participants | 40 participants |
| Sex: Female, Male Female | 12 Participants | 12 Participants | 24 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
Outcome results
Primary
AUC0-inf (Area Under the Concentration-time Curve From Time Zero to Infinity) for Ramipril.
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 |
|---|---|---|---|
| Test (Ramipril) | AUC0-inf (Area Under the Concentration-time Curve From Time Zero to Infinity) for Ramipril. | 18124.29 pg*h/mL | Standard Deviation 6270.72 |
| Reference (Altace®) | AUC0-inf (Area Under the Concentration-time Curve From Time Zero to Infinity) for Ramipril. | 18859.79 pg*h/mL | Standard Deviation 6825.69 |
90% CI: [92.73, 101.42]
Primary
AUC0-t (Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) for Ramipril.
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 |
|---|---|---|---|
| Test (Ramipril) | AUC0-t (Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) for Ramipril. | 17495.08 pg*h/mL | Standard Deviation 5964.21 |
| Reference (Altace®) | AUC0-t (Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) for Ramipril. | 18487.79 pg*h/mL | Standard Deviation 6792.41 |
90% CI: [90.82, 100.09]
Primary
Cmax (Maximum Observed Concentration of Drug Substance in Plasma)for Ramipril.
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 |
|---|---|---|---|
| Test (Ramipril) | Cmax (Maximum Observed Concentration of Drug Substance in Plasma)for Ramipril. | 21887.1 pg/mL | Standard Deviation 8460.92 |
| Reference (Altace®) | Cmax (Maximum Observed Concentration of Drug Substance in Plasma)for Ramipril. | 23640.37 pg/mL | Standard Deviation 10926.53 |
90% CI: [89.11, 103.49]
Secondary
AUC0-72 (Area Under the Concentration-time Curve From Time Zero to Time of 72 Hours) for Ramiprilat.
Informational comparison of AUc0-72 values for the metabolite Ramiprilat.
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 |
|---|---|---|---|
| Test (Ramipril) | AUC0-72 (Area Under the Concentration-time Curve From Time Zero to Time of 72 Hours) for Ramiprilat. | 164741.84 pg*h/mL | Standard Deviation 50195.92 |
| Reference (Altace®) | AUC0-72 (Area Under the Concentration-time Curve From Time Zero to Time of 72 Hours) for Ramiprilat. | 168246.84 pg*h/mL | Standard Deviation 46106.74 |
90% CI: [94.62, 100.66]
Secondary
Cmax (Maximum Observed Concentration of Drug Substance in Plasma)for Ramiprilat.
Informational comparison of Cmax values for the metabolite Ramiprilat.
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 |
|---|---|---|---|
| Test (Ramipril) | Cmax (Maximum Observed Concentration of Drug Substance in Plasma)for Ramiprilat. | 20293.09 pg/mL | Standard Deviation 14160.29 |
| Reference (Altace®) | Cmax (Maximum Observed Concentration of Drug Substance in Plasma)for Ramiprilat. | 19670.12 pg/mL | Standard Deviation 13834.13 |
90% CI: [89.34, 109.23]