Healthy Adult Male
Conditions
Brief summary
To assess the bioequivalence of OPC-41061 OD tablets and OPC-41061 conventional tablets at 15 and 30 mg in healthy adult male subjects.
Interventions
DRUGOPC-41061
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
20 Years to 39 Years
Healthy volunteers
Yes
Inclusion criteria
* Body weight of at least 50.0 kg * BMI \[body weight in kg / (height in m)2\] of at least 17.6 kg/m2 and less than 25.0 kg/m2 * Judged by the investigator or subinvestigator to be capable of providing written informed consent prior to the start of any trial-related procedures and capable of complying with the trial procedures for this study.
Exclusion criteria
* Judged by the investigator,subinvestigator, or sponsor to have a clinically significant abnormality in results of the screening examination (including a notable deviation from the site's standard values) or a medical history that could place the subject at risk or affect the evaluation of drug absorption, distribution, metabolism, or excretion * History of alcohol or drug dependence or abuse within 2 years prior to the trial * History or current infection with hepatitis or acquired immunodeficiency syndrome (AIDS) or carrier of hepatitis B positive surface antigen (HBsAg), anti-hepatitis C virus (HCV), human immunodeficiency virus (HIV), or syphilis based on the results of the Treponema pallidum (TP) antibody test or rapid plasma reagin (RPR) test * History of any severe drug allergy * Positive results in alcohol screening test or urine drug screening test at time of screening examination or trial site admission * Use of any other investigational medicinal product (IMP) within 120 days prior to Period 1 IMP administration * Consumption of any food or beverage containing St. John's wort within 14 days prior to Period 1 IMP administration * Consumption of any food or beverage containing grapefruit, Seville orange, or star fruit within 7 days prior to Period 1 IMP administration * Judgment by the investigator or subinvestigator that the subject should not participate in the study for any other reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Tolvaptan | Pre-dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 hours post-dose | Blood sampling for plasma tolvaptan concentration before IMP administration and 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 hours postdose in each period in Cohort 1 and 2 was performed for pharmacokinetic evaluation. |
| Area Under the Concentration-time Curve From Time Zero to the Last Observable Concentration at Time t (AUCt) of of Tolvaptan | Pre-dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 hours post-dose | Blood sampling for plasma tolvaptan concentration before IMP administration and 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 hours postdose in each period in Cohort 1 and 2 was performed for pharmacokinetic evaluation. |
Countries
Japan
Participant flow
Recruitment details
This single-center, open-label, randomized, 3-period 3-way, crossover study using 2 different formulations and 2 different dosing regimens investigated bioequivalence between tolvaptan orally disintegrating (OD) and conventional tablets in 84 healthy adult male subjects in 2 cohorts. Bioequivalence between the OD and conventional 15 mg tablets was investigated in Cohort 1. In Cohort 2, bioequivalence between the OD and conventional 30 mg tablets was investigated.
Pre-assignment details
A total of 84 subjects were divided into 2 cohorts of 42 subjects each. The 42 subjects each in 2 cohorts were randomly assigned to the conventional tablet first group, OD tablet with water first group, or OD tablet without water first group according to the randomization code in a 1:1:1 ratio. Forty subjects in Cohort 1 and 41 subjects in Cohort 2 completed the trial.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Subjects received single oral administration of tolvaptan 15 mg in Cohort 1, conventional or OD tablet, with or without water on each administration day in Period 1, Period 2, and Period 3.
A washout period of 72 hours was set from postdose in Period 1 until predose in Period 2 and from postdose in Period 2 until predose in Period 3. | 42 |
| Cohort 2 Subjects received single oral administration of tolvaptan 30 mg in Cohort 2, conventional or OD tablet, with or without water on each administration day in Period 1, Period 2, and Period 3.
A washout period of 72 hours was set from postdose in Period 1 until predose in Period 2 and from postdose in Period 2 until predose in Period 3. | 42 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 1 (Days 1 to 3) | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 |
| Period 2 (Days 4 to 6) | Adverse Event | 0 | 1 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 2 | Total | Cohort 1 |
|---|---|---|---|
| Age, Continuous | 23.5 years STANDARD_DEVIATION 4.8 | 24.0 years STANDARD_DEVIATION 4.5 | 24.4 years STANDARD_DEVIATION 4.3 |
| Race/Ethnicity, Customized Japanese | 42 Participants | 84 Participants | 42 Participants |
| Region of Enrollment Japan | 42 Participants | 84 Participants | 42 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 42 Participants | 84 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 41 | 0 / 41 | 0 / 42 | 0 / 42 | 0 / 41 |
| other Total, other adverse events | 1 / 41 | 1 / 41 | 2 / 41 | 1 / 42 | 0 / 42 | 0 / 41 |
| serious Total, serious adverse events | 0 / 41 | 0 / 41 | 0 / 41 | 0 / 42 | 0 / 42 | 0 / 41 |
Outcome results
Primary
Area Under the Concentration-time Curve From Time Zero to the Last Observable Concentration at Time t (AUCt) of of Tolvaptan
Blood sampling for plasma tolvaptan concentration before IMP administration and 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 hours postdose in each period in Cohort 1 and 2 was performed for pharmacokinetic evaluation.
Time frame: Pre-dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 hours post-dose
Population: Bioequivalence analysis set: all subjects with both AUCt and Cmax values across Period 1, Period 2, and Period 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: 15 mg Conventional Tablet | Area Under the Concentration-time Curve From Time Zero to the Last Observable Concentration at Time t (AUCt) of of Tolvaptan | 697 ng*h/mL | Standard Deviation 440 |
| Cohort 1: 15 mg OD Tablet Without Water | Area Under the Concentration-time Curve From Time Zero to the Last Observable Concentration at Time t (AUCt) of of Tolvaptan | 674 ng*h/mL | Standard Deviation 361 |
| Cohort 1: 15 mg OD Tablet With Water | Area Under the Concentration-time Curve From Time Zero to the Last Observable Concentration at Time t (AUCt) of of Tolvaptan | 685 ng*h/mL | Standard Deviation 392 |
| Cohort 2: 30 mg Conventional Tablet | Area Under the Concentration-time Curve From Time Zero to the Last Observable Concentration at Time t (AUCt) of of Tolvaptan | 1120 ng*h/mL | Standard Deviation 334 |
| Cohort 2: 30 mg OD Tablet Without Water | Area Under the Concentration-time Curve From Time Zero to the Last Observable Concentration at Time t (AUCt) of of Tolvaptan | 1130 ng*h/mL | Standard Deviation 306 |
| Cohort 2: 30 mg OD Tablet With Water | Area Under the Concentration-time Curve From Time Zero to the Last Observable Concentration at Time t (AUCt) of of Tolvaptan | 1110 ng*h/mL | Standard Deviation 312 |
Primary
Maximum Plasma Concentration (Cmax) of Tolvaptan
Blood sampling for plasma tolvaptan concentration before IMP administration and 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 hours postdose in each period in Cohort 1 and 2 was performed for pharmacokinetic evaluation.
Time frame: Pre-dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 hours post-dose
Population: Bioequivalence analysis set: all subjects with both AUCt and Cmax values across Period 1, Period 2, and Period 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: 15 mg Conventional Tablet | Maximum Plasma Concentration (Cmax) of Tolvaptan | 131 ng/mL | Standard Deviation 71 |
| Cohort 1: 15 mg OD Tablet Without Water | Maximum Plasma Concentration (Cmax) of Tolvaptan | 149 ng/mL | Standard Deviation 72.6 |
| Cohort 1: 15 mg OD Tablet With Water | Maximum Plasma Concentration (Cmax) of Tolvaptan | 125 ng/mL | Standard Deviation 63.1 |
| Cohort 2: 30 mg Conventional Tablet | Maximum Plasma Concentration (Cmax) of Tolvaptan | 203 ng/mL | Standard Deviation 72.7 |
| Cohort 2: 30 mg OD Tablet Without Water | Maximum Plasma Concentration (Cmax) of Tolvaptan | 218 ng/mL | Standard Deviation 56 |
| Cohort 2: 30 mg OD Tablet With Water | Maximum Plasma Concentration (Cmax) of Tolvaptan | 198 ng/mL | Standard Deviation 54.7 |