Healthy
Conditions
Brief summary
This study is being conducted to determine if 5 mg amlodipine 3rd Orally-Disintegrating (OD) tablet (new formulation) and 5 mg amlodipine 2nd OD tablet (commercial formulation) are bioequivalent.
Interventions
DRUGAmlodipine
3rd OD 5 mg tablet single oral dose administered with water
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
20 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy; * Body Mass Index (BMI) of 18 to 28 kg/m2; * total body weight within the range of 50 to 100 kg
Exclusion criteria
* History of regular alcohol consumption exceeding 14 drinks/week * Use of tobacco- or nicotine-containing products in excess of the equivalent of 10 cigarettes per day
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-Time Curve From Zero Time Until the Last Sampling Time (AUCt) | prior to dosing, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120 and 144 hours post dose | Area under the concentration-time curve from zero time until the last sampling time |
| Maximum Observed Plasma Concentration (Cmax) | prior to dosing, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120 and 144 hours post dose | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Terminal Elimination Half-Life (T-half) | prior to dosing, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120 and 144 hours post dose | Terminal phase half-life calculated as ln(2) / kel |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast), Area Under the Plasma Concentration-Time Curve to Infinity (AUCinf) | prior to dosing, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120 and 144 hours post dose | AUC last = Area under the concentration versus time curve from zero time until the last measurable concentration is calculated using the trapezoidal rule. AUCinf = AUClast + (Ct / kel), where Ct is the estimated concentration at the last measurable concentration. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | prior to dosing, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120 and 144 hours post dose | — |
| Mean Residence Time (MRT) | prior to dosing, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120 and 144 hours post dose | MRT = AUMCinf / AUCinf, where AUMCinf is the area under the first moment curve from zero time to infinity calculated as AUMCinf = AUMCt + ((t x Ct) / kel) + (Ct / kel\^2). AUMCt is the area under the first moment curve from zero time to time t calculated using the trapezoidal method. |
| Apparent Terminal Elimination Phase Rate Constant (Kel) | prior to dosing, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120 and 144 hours post dose | Estimated as the absolute value of the slope of a linear regression during the terminal phase of the natural-logarithm (ln) transformed concentration-time profile. |
Countries
Japan
Participant flow
Recruitment details
Participants were screened at one center in Japan.
Pre-assignment details
This study consisted of 2 cohorts (I and II). The design of each cohort was an open-label, randomized, 2-periods, crossover, single-dose study in healthy adult male subjects. A washout period of at least 14 days was taken between each administration in Periods 1 and 2.
Participants by arm
| Arm | Count |
|---|---|
| 3rd OD Tablet With Water, Then 2nd OD Tablet With Water One amlodipine third generation orally disintegrating (OD) 5 mg tablet (test) taken with water during the first intervention period, then one amlodipine second generation OD 5 mg tablet (reference) taken with water during the second intervention period. A washout of 14 days was retained between periods. | 12 |
| 2nd OD Tablet With Water, Then 3rd OD Tablet With Water One amlodipine second generation OD 5mg tablet (reference) taken with water during the first intervention period, then one amlodipine third generation OD 5 mg tablet (test) taken with water during the second intervention period. A washout of 14 days was retained between periods. | 12 |
| 3rd OD Tablet Without Water, Then 2nd OD Tablet Without Water One amlodipine third generation OD 5 mg tablet (test) taken without water during the first intervention period, then one amlodipine second generation OD 5 mg tablet (reference) taken without water during the second intervention period. A washout of 14 days was retained between periods. | 12 |
| 2nd OD Tablet Without Water, Then 3rd OD Tablet Without Water One amlodipine second generation OD 5mg tablet (reference) taken without water during the first intervention period, then one amlodipine third generation OD 5 mg tablet (test) taken without water during the second intervention period. A washout of 14 days was retained between periods. | 12 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Washout | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | 3rd OD Tablet With Water, Then 2nd OD Tablet With Water | 2nd OD Tablet With Water, Then 3rd OD Tablet With Water | 3rd OD Tablet Without Water, Then 2nd OD Tablet Without Water | 2nd OD Tablet Without Water, Then 3rd OD Tablet Without Water | Total |
|---|---|---|---|---|---|
| Age, Continuous | 33.8 years STANDARD_DEVIATION 10.7 | 32.4 years STANDARD_DEVIATION 11.1 | 37.3 years STANDARD_DEVIATION 9 | 37.8 years STANDARD_DEVIATION 12.1 | 33.1 years STANDARD_DEVIATION 10.7 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 12 Participants | 12 Participants | 12 Participants | 12 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 23 | 6 / 24 | 2 / 24 | 3 / 24 |
| serious Total, serious adverse events | 0 / 23 | 0 / 24 | 0 / 24 | 0 / 24 |
Outcome results
Primary
Area Under the Concentration-Time Curve From Zero Time Until the Last Sampling Time (AUCt)
Area under the concentration-time curve from zero time until the last sampling time
Time frame: prior to dosing, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120 and 144 hours post dose
Population: The PK parameter analysis set was defined as all subjects randomized and treated who completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: 3rd OD Tablet (Test) With Water | Area Under the Concentration-Time Curve From Zero Time Until the Last Sampling Time (AUCt) | 126.36 ng*h/mL | Standard Deviation 33.16 |
| Cohort I: 2nd OD Tablet (Reference) With Water | Area Under the Concentration-Time Curve From Zero Time Until the Last Sampling Time (AUCt) | 129.48 ng*h/mL | Standard Deviation 39.93 |
| Cohort II: 3rd OD Tablet (Test) Without Water | Area Under the Concentration-Time Curve From Zero Time Until the Last Sampling Time (AUCt) | 122.33 ng*h/mL | Standard Deviation 32.59 |
| Cohort II: 2nd OD Tablet (Reference) Without Water | Area Under the Concentration-Time Curve From Zero Time Until the Last Sampling Time (AUCt) | 119.75 ng*h/mL | Standard Deviation 28.23 |
Comparison: Natural log transformed AUCt was analyzed using a mixed effects model with sequence, period and formulation as fixed effects and subject within sequence as a random effect. Adjusted mean difference (test - reference) and 90% CI was obtained from the model and exponentiated to provide estimates of the ratio of adjusted geometric mean and 90% CI for the ratio. Alternative hypothesis of bioequivalence: (H1: θL \<=µT - µR \<=θU); null hypothesis of inequivalence: (Ho: µT - µR \<θL or µT - µR \>θU).90% CI: [93.09, 104.46]
Comparison: Natural log transformed AUCt was analyzed using a mixed effects model with sequence, period and formulation as fixed effects and subject within sequence as a random effect. Adjusted mean difference (test - reference) and 90% CI was obtained from the model and exponentiated to provide estimates of the ratio of adjusted geometric mean and 90% CI for the ratio. Alternative hypothesis of bioequivalence: (H1: θL \<=µT - µR \<=θU); null hypothesis of inequivalence: (Ho: µT - µR \<θL or µT - µR \>θU).90% CI: [97.28, 105.45]
Primary
Maximum Observed Plasma Concentration (Cmax)
Time frame: prior to dosing, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120 and 144 hours post dose
Population: The PK parameter analysis set was defined as all subjects randomized and treated who completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: 3rd OD Tablet (Test) With Water | Maximum Observed Plasma Concentration (Cmax) | 2.70 ng/mL | Standard Deviation 0.513 |
| Cohort I: 2nd OD Tablet (Reference) With Water | Maximum Observed Plasma Concentration (Cmax) | 2.74 ng/mL | Standard Deviation 0.65 |
| Cohort II: 3rd OD Tablet (Test) Without Water | Maximum Observed Plasma Concentration (Cmax) | 2.48 ng/mL | Standard Deviation 0.47 |
| Cohort II: 2nd OD Tablet (Reference) Without Water | Maximum Observed Plasma Concentration (Cmax) | 2.45 ng/mL | Standard Deviation 0.409 |
Comparison: Natural log transformed Cmax was analyzed using a mixed effects model with sequence, period and formulation as fixed effects and subject within sequence as a random effect. Adjusted mean difference (test - reference) and 90% CI was obtained from the model and exponentiated to provide estimates of the ratio of adjusted geometric mean and 90% CI for the ratio. Alternative hypothesis of bioequivalence: (H1: θL \<=µT - µR \<=θU); null hypothesis of inequivalence: (Ho: µT - µR \<θL or µT - µR \>θU).90% CI: [92.28, 106.28]
Comparison: Natural log transformed Cmax was analyzed using a mixed effects model with sequence, period and formulation as fixed effects and subject within sequence as a random effect. Adjusted mean difference (test - reference) and 90% CI was obtained from the model and exponentiated to provide estimates of the ratio of adjusted geometric mean and 90% CI for the ratio. Alternative hypothesis of bioequivalence: (H1: θL \<=µT - µR \<=θU); null hypothesis of inequivalence: (Ho: µT - µR \<θL or µT - µR \>θU).90% CI: [95.93, 106]
Secondary
Apparent Terminal Elimination Half-Life (T-half)
Terminal phase half-life calculated as ln(2) / kel
Time frame: prior to dosing, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120 and 144 hours post dose
Population: The PK parameter analysis set was defined as all subjects randomized and treated who completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: 3rd OD Tablet (Test) With Water | Apparent Terminal Elimination Half-Life (T-half) | 41.45 hour | Standard Deviation 9.76 |
| Cohort I: 2nd OD Tablet (Reference) With Water | Apparent Terminal Elimination Half-Life (T-half) | 40.27 hour | Standard Deviation 8.48 |
| Cohort II: 3rd OD Tablet (Test) Without Water | Apparent Terminal Elimination Half-Life (T-half) | 45.04 hour | Standard Deviation 10.16 |
| Cohort II: 2nd OD Tablet (Reference) Without Water | Apparent Terminal Elimination Half-Life (T-half) | 46.20 hour | Standard Deviation 8.85 |
Secondary
Apparent Terminal Elimination Phase Rate Constant (Kel)
Estimated as the absolute value of the slope of a linear regression during the terminal phase of the natural-logarithm (ln) transformed concentration-time profile.
Time frame: prior to dosing, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120 and 144 hours post dose
Population: The PK parameter analysis set was defined as all subjects randomized and treated who completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: 3rd OD Tablet (Test) With Water | Apparent Terminal Elimination Phase Rate Constant (Kel) | 0.0174 L/h | Standard Deviation 0.0031 |
| Cohort I: 2nd OD Tablet (Reference) With Water | Apparent Terminal Elimination Phase Rate Constant (Kel) | 0.0179 L/h | Standard Deviation 0.0035 |
| Cohort II: 3rd OD Tablet (Test) Without Water | Apparent Terminal Elimination Phase Rate Constant (Kel) | 0.0162 L/h | Standard Deviation 0.0041 |
| Cohort II: 2nd OD Tablet (Reference) Without Water | Apparent Terminal Elimination Phase Rate Constant (Kel) | 0.0156 L/h | Standard Deviation 0.0031 |
Secondary
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast), Area Under the Plasma Concentration-Time Curve to Infinity (AUCinf)
AUC last = Area under the concentration versus time curve from zero time until the last measurable concentration is calculated using the trapezoidal rule. AUCinf = AUClast + (Ct / kel), where Ct is the estimated concentration at the last measurable concentration.
Time frame: prior to dosing, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120 and 144 hours post dose
Population: The PK parameter analysis set was defined as all subjects randomized and treated who completed the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort I: 3rd OD Tablet (Test) With Water | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast), Area Under the Plasma Concentration-Time Curve to Infinity (AUCinf) | AUClast | 124.14 ng*h/mL | Standard Deviation 33.96 |
| Cohort I: 3rd OD Tablet (Test) With Water | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast), Area Under the Plasma Concentration-Time Curve to Infinity (AUCinf) | AUCinf | 142.87 ng*h/mL | Standard Deviation 43.2 |
| Cohort I: 2nd OD Tablet (Reference) With Water | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast), Area Under the Plasma Concentration-Time Curve to Infinity (AUCinf) | AUCinf | 145.22 ng*h/mL | Standard Deviation 49.19 |
| Cohort I: 2nd OD Tablet (Reference) With Water | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast), Area Under the Plasma Concentration-Time Curve to Infinity (AUCinf) | AUClast | 127.36 ng*h/mL | Standard Deviation 40.91 |
| Cohort II: 3rd OD Tablet (Test) Without Water | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast), Area Under the Plasma Concentration-Time Curve to Infinity (AUCinf) | AUClast | 121.05 ng*h/mL | Standard Deviation 33.76 |
| Cohort II: 3rd OD Tablet (Test) Without Water | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast), Area Under the Plasma Concentration-Time Curve to Infinity (AUCinf) | AUCinf | 140.41 ng*h/mL | Standard Deviation 42.18 |
| Cohort II: 2nd OD Tablet (Reference) Without Water | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast), Area Under the Plasma Concentration-Time Curve to Infinity (AUCinf) | AUClast | 118.27 ng*h/mL | Standard Deviation 29.43 |
| Cohort II: 2nd OD Tablet (Reference) Without Water | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast), Area Under the Plasma Concentration-Time Curve to Infinity (AUCinf) | AUCinf | 138.14 ng*h/mL | Standard Deviation 34.1 |
Secondary
Mean Residence Time (MRT)
MRT = AUMCinf / AUCinf, where AUMCinf is the area under the first moment curve from zero time to infinity calculated as AUMCinf = AUMCt + ((t x Ct) / kel) + (Ct / kel\^2). AUMCt is the area under the first moment curve from zero time to time t calculated using the trapezoidal method.
Time frame: prior to dosing, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120 and 144 hours post dose
Population: The PK parameter analysis set was defined as all subjects randomized and treated who completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort I: 3rd OD Tablet (Test) With Water | Mean Residence Time (MRT) | 61.29 hour | Standard Deviation 13.55 |
| Cohort I: 2nd OD Tablet (Reference) With Water | Mean Residence Time (MRT) | 59.77 hour | Standard Deviation 11.99 |
| Cohort II: 3rd OD Tablet (Test) Without Water | Mean Residence Time (MRT) | 66.18 hour | Standard Deviation 14.1 |
| Cohort II: 2nd OD Tablet (Reference) Without Water | Mean Residence Time (MRT) | 67.33 hour | Standard Deviation 11.9 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time frame: prior to dosing, 2, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96, 120 and 144 hours post dose
Population: The PK parameter analysis set was defined as all subjects randomized and treated who completed the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort I: 3rd OD Tablet (Test) With Water | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 8 hour |
| Cohort I: 2nd OD Tablet (Reference) With Water | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 8 hour |
| Cohort II: 3rd OD Tablet (Test) Without Water | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 8 hour |
| Cohort II: 2nd OD Tablet (Reference) Without Water | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 8 hour |