Healthy
Conditions
Keywords
Bioequivalence, Healthy Subjects
Brief summary
The object of this study was to compare the relative bioavailability (rate and extent of absorption) of 100/25 mg Losartan potassium/Hydrochlorothiazide Tablets manufactured by Teva Pharmaceutical Industries Ltd. and distributed by Teva Pharmaceuticals USA with that of Hyzaar® 100/25 mg Tablets distributed by Merck & Co., Inc. following a single oral dose (1 x 100/25 mg tablet) in healthy adult subjects administered under fasting conditions.
Detailed description
Criteria for Evaluation: FDA Bioequivalence Criteria Statistical Methods: FDA Bioequivalence Statistical Methods
Interventions
100/25 mg Tablets
DRUGHyzaar®
100/25 mg Tablets
Sponsors
Teva Pharmaceuticals USA
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy men and women, 18-45 years of age (inclusive). * Body mass index should be less than or equal to 30 * Screening procedures completed within 28 days prior to dosing. * If female and: * of child bearing potential, is practicing an acceptable barrier method of birth control for the duration of the study * is postmenopausal for at least 1 year * is surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy)
Exclusion criteria
* Subjects with a recent history of drug or alcohol abuse or addiction. * 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 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 the study. * Female subjects demonstrating a positive pregnancy screen. * Female subjects who are currently breastfeeding. * Subjects who have used implanted or injected hormonal contraceptives anytime during the 180 days prior to study dosing or hormonal contraceptives within 14 days of dosing will not be allowed to participate. * Subjects with a history of allergic response(s) to losartan, hydrochlorothiazide 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 dosing (as determined by the clinical investigators). * Subjects who have taken any drug known to induce or inhibit hepatic drug metabolism in the 28 days prior to dosing. * Subjects who have used tobacco products within 90 days of Period 1 dose administration. * Subjects who report donating greater than 150 mL of blood within 14 days prior to dosing. * Subjects who report receiving any investigational drug within 28 days prior to dosing. * Subjects who report taking any systemic prescription medication in the 14 days prior to dosing. * Subjects who report an intolerance of direct venipuncture. * Subjects who report consuming an abnormal diet within the 28 days prior to dosing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-inf of Hydrochlorothiazide(Area Under the Concentration-time Curve From Time Zero to Infinity) | Blood samples collected over a 48 hour period. | Bioequivalence based on Hydrochlorothiazide AUC0-inf. |
| AUC0-inf of Losartan(Area Under the Concentration-time Curve From Time Zero to Infinity) | Blood samples collected over a 48 hour period. | Bioequivalence based on Losartan AUC0-inf. |
| Cmax of Hydroclorothiazide(Maximum Observed Concentration of Drug Substance in Plasma) | Blood samples collected over a 48 hour period. | Bioequivalence based on Hydrochlorothiazide Cmax. |
| AUC0-t of Hydrochlorothiazide(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Blood samples collected over a 48 hour period. | Bioequivalence based on Hydrochlorothiazide AUC0-t. |
| Cmax of Losartan(Maximum Observed Concentration of Drug Substance in Plasma) | Blood samples collected over a 48 hour period. | Bioequivalence based on Losartan Cmax. |
| AUC0-t of Losartan(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Blood samples collected over a 48 hour period. | Bioequivalence based on Losartan AUC0-t. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-t of Losartan Carboxy Acid(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Blood samples collected over a 48 hour period. | Informational comparison of AUC0-t values for the metabolite Losartan Carboxy Acid. |
| AUC0-inf of Losartan Carboxy Acid(Area Under the Concentration-time Curve From Time Zero to Infinity) | Blood samples collected over a 48 hour period. | Informational comparison of AUC0-inf values for the metabolite Losartan Carboxy Acid. |
| Cmax of Losartan Carboxy Acid(Maximum Observed Concentration of Drug Substance in Plasma) | Blood samples collected over a 48 hour period. | Informational comparison of Cmax values for the metabolite Losartan Carboxy Acid. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Losartan/HCTZ (Test) First 100/25 mg Losartan potassium/Hydrochlorothiazide Tablets test product dosed in first period followed by 100/25 mg Hyzaar® Tablets reference product dosed in the second period. | 10 |
| Hyzaar® (Reference) First 100/25 mg Hyzaar® Tablets reference product dosed in first period followed by 100/25 mg Losartan potassium/Hydrochlorothiazide Tablets test product dosed in the second period. | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Losartan/HCTZ (Test) First | Hyzaar® (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 | 10 Participants | 10 Participants | 20 Participants |
| Race/Ethnicity, Customized American Indian | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 9 participants | 8 participants | 17 participants |
| Region of Enrollment United States | 10 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 8 Participants | 9 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 20 | 6 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
AUC0-inf of Hydrochlorothiazide(Area Under the Concentration-time Curve From Time Zero to Infinity)
Bioequivalence based on Hydrochlorothiazide AUC0-inf.
Time frame: Blood samples collected over a 48 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan/HCTZ (Test) | AUC0-inf of Hydrochlorothiazide(Area Under the Concentration-time Curve From Time Zero to Infinity) | 1087.64 ng*h/mL | Standard Deviation 240.82 |
| Hyzaar® (Reference) | AUC0-inf of Hydrochlorothiazide(Area Under the Concentration-time Curve From Time Zero to Infinity) | 1030.73 ng*h/mL | Standard Deviation 238.96 |
90% CI: [99.64, 111.82]
Primary
AUC0-inf of Losartan(Area Under the Concentration-time Curve From Time Zero to Infinity)
Bioequivalence based on Losartan AUC0-inf.
Time frame: Blood samples collected over a 48 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan/HCTZ (Test) | AUC0-inf of Losartan(Area Under the Concentration-time Curve From Time Zero to Infinity) | 880.15 ng*h/mL | Standard Deviation 368.58 |
| Hyzaar® (Reference) | AUC0-inf of Losartan(Area Under the Concentration-time Curve From Time Zero to Infinity) | 877.99 ng*h/mL | Standard Deviation 362.75 |
90% CI: [93.1, 106.12]
Primary
AUC0-t of Hydrochlorothiazide(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Bioequivalence based on Hydrochlorothiazide AUC0-t.
Time frame: Blood samples collected over a 48 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan/HCTZ (Test) | AUC0-t of Hydrochlorothiazide(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | 1057.58 ng*h/mL | Standard Deviation 231.26 |
| Hyzaar® (Reference) | AUC0-t of Hydrochlorothiazide(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | 1001.54 ng*h/mL | Standard Deviation 236 |
90% CI: [99.58, 112.41]
Primary
AUC0-t of Losartan(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Bioequivalence based on Losartan AUC0-t.
Time frame: Blood samples collected over a 48 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan/HCTZ (Test) | AUC0-t of Losartan(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | 866.88 ng*h/mL | Standard Deviation 366.15 |
| Hyzaar® (Reference) | AUC0-t of Losartan(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | 865.00 ng*h/mL | Standard Deviation 362.86 |
90% CI: [93.15, 106.18]
Primary
Cmax of Hydroclorothiazide(Maximum Observed Concentration of Drug Substance in Plasma)
Bioequivalence based on Hydrochlorothiazide Cmax.
Time frame: Blood samples collected over a 48 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan/HCTZ (Test) | Cmax of Hydroclorothiazide(Maximum Observed Concentration of Drug Substance in Plasma) | 177.63 ng/mL | Standard Deviation 48.09 |
| Hyzaar® (Reference) | Cmax of Hydroclorothiazide(Maximum Observed Concentration of Drug Substance in Plasma) | 161.56 ng/mL | Standard Deviation 53.75 |
90% CI: [101.47, 122.79]
Primary
Cmax of Losartan(Maximum Observed Concentration of Drug Substance in Plasma)
Bioequivalence based on Losartan Cmax.
Time frame: Blood samples collected over a 48 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan/HCTZ (Test) | Cmax of Losartan(Maximum Observed Concentration of Drug Substance in Plasma) | 509.63 ng/mL | Standard Deviation 314.75 |
| Hyzaar® (Reference) | Cmax of Losartan(Maximum Observed Concentration of Drug Substance in Plasma) | 538.11 ng/mL | Standard Deviation 298.89 |
90% CI: [80.2, 108.88]
Secondary
AUC0-inf of Losartan Carboxy Acid(Area Under the Concentration-time Curve From Time Zero to Infinity)
Informational comparison of AUC0-inf values for the metabolite Losartan Carboxy Acid.
Time frame: Blood samples collected over a 48 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan/HCTZ (Test) | AUC0-inf of Losartan Carboxy Acid(Area Under the Concentration-time Curve From Time Zero to Infinity) | 4281.32 ng*h/mL | Standard Deviation 1182.77 |
| Hyzaar® (Reference) | AUC0-inf of Losartan Carboxy Acid(Area Under the Concentration-time Curve From Time Zero to Infinity) | 4164.62 ng*h/mL | Standard Deviation 1096.64 |
90% CI: [98.72, 106.01]
Secondary
AUC0-t of Losartan Carboxy Acid(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Informational comparison of AUC0-t values for the metabolite Losartan Carboxy Acid.
Time frame: Blood samples collected over a 48 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan/HCTZ (Test) | AUC0-t of Losartan Carboxy Acid(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | 4236.78 ng*h/mL | Standard Deviation 1176.34 |
| Hyzaar® (Reference) | AUC0-t of Losartan Carboxy Acid(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | 4117.07 ng*h/mL | Standard Deviation 1087.67 |
90% CI: [98.75, 106.14]
Secondary
Cmax of Losartan Carboxy Acid(Maximum Observed Concentration of Drug Substance in Plasma)
Informational comparison of Cmax values for the metabolite Losartan Carboxy Acid.
Time frame: Blood samples collected over a 48 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Losartan/HCTZ (Test) | Cmax of Losartan Carboxy Acid(Maximum Observed Concentration of Drug Substance in Plasma) | 726.85 ng/mL | Standard Deviation 210.78 |
| Hyzaar® (Reference) | Cmax of Losartan Carboxy Acid(Maximum Observed Concentration of Drug Substance in Plasma) | 675.54 ng/mL | Standard Deviation 197.25 |
90% CI: [98.96, 115.23]