Healthy Adult Subjects
Conditions
Brief summary
To evaluate the single-dose bioequivalence of oral suspension and intravenous (IV) formulation of edaravone in the fasting state in healthy adult subjects
Sponsors
Shionogi
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy adult male or female volunteers * Japanese * Subjects aged between 20 and 45 years at the time of informed consent * Subjects who have thoroughly understood the contents of the study and voluntarily provided written informed consent to participate in the study
Exclusion criteria
Additional screening criteria check may apply for qualification: * Subjects with a current or previous history of cardiac, hepatic, renal, gastrointestinal, respiratory, psychiatric/nervous, hematopoietic, or endocrine diseases, and those whom the investigator (or subinvestigator) deems unsuitable for the study * Body mass index (BMI) of \<18.0 or \>30.0, or body weight of \<50 kg (BMI formula: body weight \[kg\]/height \[m\]2, rounded to one decimal place) * Subjects who have undergone any surgery known to affect the gastrointestinal absorption of drugs * Female subjects who do not agree to use an effective method of contraception from screening or 2 weeks before the start of investigational product administration, whichever comes earlier, to 14 days after the completion (or discontinuation) of investigational product administration. Male subjects who do not agree to use an effective method of contraception from the start of investigational product administration to 14 days after the completion (or discontinuation) of investigational product administration * Subjects who have previously received edaravone * Subjects who have participated in another clinical study and received an investigational product within 12 weeks before providing informed consent
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Area Under the Plasma Concentration Versus Time Curve From Time Zero up to the Last Quantifiable Concentration Time-point (AUC0-t) of Unchanged Edaravone After Oral and Intravenous Administration | The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs. |
| Area Under the Plasma Concentration Versus Time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase (AUC0-inf) of Unchanged Edaravone After Oral and Intravenous Administration | The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs. |
| Maximum Plasma Concentration (Cmax) of Unchanged Edaravone After Oral and Intravenous Administration | The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Maximum Plasma Concentration (Tmax) | The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs. | — |
| Area Under the Plasma Concentration Versus Time Curve From Time Zero up to 24 Hours (AUC0-24) | The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; Day 2 at 24 hrs ; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75,2, 3, 4, 6, 8, 12 hrs; Day 2 at 24 hrs. | — |
| Area Under the Plasma Concentration Versus Time Curve From Time Zero up to the Last Sampling Time-point (for All Time-points) (AUC0-all) | The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs. | — |
| Terminal Elimination Half-life (t1/2) | The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs. | — |
| Elimination Rate Constant From the Central Compartment (Kel) | The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs. | — |
| Mean Residence Time From Time Zero up to Infinity With Extrapolation of the Terminal Phase (MRT0-inf) of Unchanged Edaravone | The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs. | — |
| Total Clearance (CL) of Unchanged Edaravone After Intravenous Administration | The date of dosing is defined as Day 1. Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Day 2 at 24, 36 hrs; Day 3 at 48 hrs. | — |
| Volume of Distribution During Terminal Phase (Vz) of Unchanged Edaravone After Intravenous Administration | The date of dosing is defined as Day 1. Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Day 2 at 24, 36 hrs; Day 3 at 48 hrs. | — |
| Volume of Distribution at Steady State (Vss) of Unchanged Edaravone After Intravenous Administration | The date of dosing is defined as Day 1. Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Day 2 at 24, 36 hrs; Day 3 at 48 hrs. | — |
| Apparent Total Clearance (CL/F) of Unchanged Edaravone After Oral Administration | The date of dosing is defined as Day 1. Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; Day 2 at 24, 36 hrs; Day 3 at 48 hrs. | — |
| Apparent Volume of Distribution During Terminal Phase (Vz/F) of Unchanged Edaravone After Oral Administration | The date of dosing is defined as Day 1. Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; Day 2 at 24, 36 hrs; Day 3 at 48 hrs. | — |
| Apparent Volume of Distribution at Steady State (Vss/F) of Unchanged Edaravone After Oral Administration | The date of dosing is defined as Day 1. Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; Day 2 at 24, 36 hrs; Day 3 at 48 hrs. | — |
| Cumulative Amount of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48) | Urine samples are collected: Day1 to 6. | — |
| Cumulative Percentage of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48) | Urine samples are collected: Day1 to 6. | — |
| Renal Clearance (CLr) of Unchanged Edaravone | Urine samples are collected: Day1 to 6. | — |
| Bioavailability (F) of Unchanged Edaravone After Oral Administration | PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, and 12 hrs; Day 2 at 24 and 36 hrs; Day 3 at 48 hrs. IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75,2, 3, 4, 6, 8, 12 hrs; Day 2 at 24 and 36 hrs; Day 3 at 48hrs. | Bioavailability was calculated from ratio of AUC0-inf of unchanged edaravone after oral and intravenous administration. |
| AUC0-t of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs. | — |
| AUC0-inf of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs. | — |
| Cmax of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs. | — |
| Number of Participants With Adverse Events and Adverse Drug Reactions | Day 1 to 11 | — |
Countries
Japan
Contacts
STUDY_DIRECTORShionogi Clinical Trials Administrator Clinical Support Help Line
Shionogi
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Edaravone Oral Suspensione First, Then Edaravone IV Formulation Period 1: a single dose of Edaravone oral suspension (105 mg) . Period 2: a single dose of Edaravone IV formulation (60 mg/60 min). | 21 |
| Edaravone IV Formulation First, Then Edaravone Oral Suspension Period 1: a single dose of Edaravone IV formulation (60 mg/60 min). Period 2: a single dose of Edaravone oral suspension (105 mg) . | 21 |
| Total | 42 |
Baseline characteristics
| Characteristic | Edaravone Oral Suspensione First, Then Edaravone IV Formulation | Edaravone IV Formulation First, Then Edaravone Oral Suspension | 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 | 21 Participants | 21 Participants | 42 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 21 Participants | 21 Participants | 42 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 14 Participants | 14 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 42 | 0 / 42 |
| other Total, other adverse events | 1 / 42 | 1 / 42 |
| serious Total, serious adverse events | 0 / 42 | 0 / 42 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase (AUC0-inf) of Unchanged Edaravone After Oral and Intravenous Administration
Time frame: The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Edaravone Oral Suspension | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase (AUC0-inf) of Unchanged Edaravone After Oral and Intravenous Administration | 1762 ng·h/mL | Standard Deviation 540 |
| Edaravone IV Formulation | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase (AUC0-inf) of Unchanged Edaravone After Oral and Intravenous Administration | 1736 ng·h/mL | Standard Deviation 331 |
90% CI: [0.92, 1.04]
Primary
Area Under the Plasma Concentration Versus Time Curve From Time Zero up to the Last Quantifiable Concentration Time-point (AUC0-t) of Unchanged Edaravone After Oral and Intravenous Administration
Time frame: The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Edaravone Oral Suspension | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to the Last Quantifiable Concentration Time-point (AUC0-t) of Unchanged Edaravone After Oral and Intravenous Administration | 1743 ng·h/mL | Standard Deviation 534 |
| Edaravone IV Formulation | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to the Last Quantifiable Concentration Time-point (AUC0-t) of Unchanged Edaravone After Oral and Intravenous Administration | 1720 ng·h/mL | Standard Deviation 326 |
90% CI: [0.91, 1.04]
Primary
Maximum Plasma Concentration (Cmax) of Unchanged Edaravone After Oral and Intravenous Administration
Time frame: The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Edaravone Oral Suspension | Maximum Plasma Concentration (Cmax) of Unchanged Edaravone After Oral and Intravenous Administration | 1656 ng/mL | Standard Deviation 733.6 |
| Edaravone IV Formulation | Maximum Plasma Concentration (Cmax) of Unchanged Edaravone After Oral and Intravenous Administration | 1253 ng/mL | Standard Deviation 228.9 |
90% CI: [1.09, 1.36]
Secondary
Apparent Total Clearance (CL/F) of Unchanged Edaravone After Oral Administration
Time frame: The date of dosing is defined as Day 1. Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Edaravone Oral Suspension | Apparent Total Clearance (CL/F) of Unchanged Edaravone After Oral Administration | 67.9 L/h | Standard Deviation 30.1 |
Secondary
Apparent Volume of Distribution at Steady State (Vss/F) of Unchanged Edaravone After Oral Administration
Time frame: The date of dosing is defined as Day 1. Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Edaravone Oral Suspension | Apparent Volume of Distribution at Steady State (Vss/F) of Unchanged Edaravone After Oral Administration | 164.0 L | Standard Deviation 78.9 |
Secondary
Apparent Volume of Distribution During Terminal Phase (Vz/F) of Unchanged Edaravone After Oral Administration
Time frame: The date of dosing is defined as Day 1. Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Edaravone Oral Suspension | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Unchanged Edaravone After Oral Administration | 826 L | Standard Deviation 618 |
Secondary
Area Under the Plasma Concentration Versus Time Curve From Time Zero up to 24 Hours (AUC0-24)
Time frame: The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; Day 2 at 24 hrs ; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75,2, 3, 4, 6, 8, 12 hrs; Day 2 at 24 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Edaravone Oral Suspension | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to 24 Hours (AUC0-24) | Unchanged edaravone | 1735 ng·h/mL | Standard Deviation 523 |
| Edaravone Oral Suspension | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to 24 Hours (AUC0-24) | Sulfate conjugate | 19837 ng·h/mL | Standard Deviation 5185 |
| Edaravone Oral Suspension | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to 24 Hours (AUC0-24) | Glucuronide Conjugate | 3917 ng·h/mL | Standard Deviation 727 |
| Edaravone IV Formulation | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to 24 Hours (AUC0-24) | Unchanged edaravone | 1714 ng·h/mL | Standard Deviation 317 |
| Edaravone IV Formulation | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to 24 Hours (AUC0-24) | Sulfate conjugate | 14830 ng·h/mL | Standard Deviation 3519 |
| Edaravone IV Formulation | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to 24 Hours (AUC0-24) | Glucuronide Conjugate | 2288 ng·h/mL | Standard Deviation 479 |
Secondary
Area Under the Plasma Concentration Versus Time Curve From Time Zero up to the Last Sampling Time-point (for All Time-points) (AUC0-all)
Time frame: The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Edaravone Oral Suspension | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to the Last Sampling Time-point (for All Time-points) (AUC0-all) | Unchanged edaravone | 1752 ng·h/mL | Standard Deviation 532 |
| Edaravone Oral Suspension | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to the Last Sampling Time-point (for All Time-points) (AUC0-all) | Sulfate conjugate | 20035 ng·h/mL | Standard Deviation 5252 |
| Edaravone Oral Suspension | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to the Last Sampling Time-point (for All Time-points) (AUC0-all) | Glucuronide Conjugate | 3927 ng·h/mL | Standard Deviation 730 |
| Edaravone IV Formulation | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to the Last Sampling Time-point (for All Time-points) (AUC0-all) | Unchanged edaravone | 1727 ng·h/mL | Standard Deviation 323 |
| Edaravone IV Formulation | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to the Last Sampling Time-point (for All Time-points) (AUC0-all) | Sulfate conjugate | 15025 ng·h/mL | Standard Deviation 3575 |
| Edaravone IV Formulation | Area Under the Plasma Concentration Versus Time Curve From Time Zero up to the Last Sampling Time-point (for All Time-points) (AUC0-all) | Glucuronide Conjugate | 2297 ng·h/mL | Standard Deviation 481 |
Secondary
AUC0-inf of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration
Time frame: The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Edaravone Oral Suspension | AUC0-inf of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | Sulfate conjugate | 20055 ng·h/mL | Standard Deviation 5256 |
| Edaravone Oral Suspension | AUC0-inf of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | Glucuronide conjugate | 3924 ng·h/mL | Standard Deviation 731 |
| Edaravone IV Formulation | AUC0-inf of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | Sulfate conjugate | 15055 ng·h/mL | Standard Deviation 3579 |
| Edaravone IV Formulation | AUC0-inf of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | Glucuronide conjugate | 2295 ng·h/mL | Standard Deviation 482 |
Secondary
AUC0-t of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration
Time frame: The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Edaravone Oral Suspension | AUC0-t of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | Sulfate conjugate | 20031 ng·h/mL | Standard Deviation 5255 |
| Edaravone Oral Suspension | AUC0-t of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | Glucuronide Conjugate | 3914 ng·h/mL | Standard Deviation 730 |
| Edaravone IV Formulation | AUC0-t of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | Sulfate conjugate | 15024 ng·h/mL | Standard Deviation 3576 |
| Edaravone IV Formulation | AUC0-t of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | Glucuronide Conjugate | 2285 ng·h/mL | Standard Deviation 481 |
Secondary
Bioavailability (F) of Unchanged Edaravone After Oral Administration
Bioavailability was calculated from ratio of AUC0-inf of unchanged edaravone after oral and intravenous administration.
Time frame: PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, and 12 hrs; Day 2 at 24 and 36 hrs; Day 3 at 48 hrs. IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75,2, 3, 4, 6, 8, 12 hrs; Day 2 at 24 and 36 hrs; Day 3 at 48hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Edaravone Oral Suspension | Bioavailability (F) of Unchanged Edaravone After Oral Administration | 57.3 percentage bioavailability | Standard Deviation 12.6 |
Secondary
Cmax of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration
Time frame: The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Edaravone Oral Suspension | Cmax of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | Sulfate conjugate | 7291 ng/mL | Standard Deviation 1898 |
| Edaravone Oral Suspension | Cmax of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | Glucuronide conjugate | 2237 ng/mL | Standard Deviation 388 |
| Edaravone IV Formulation | Cmax of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | Sulfate conjugate | 4843 ng/mL | Standard Deviation 817.8 |
| Edaravone IV Formulation | Cmax of Sulfate and Glucuronide Conjugates After Oral and Intravenous Administration | Glucuronide conjugate | 1012 ng/mL | Standard Deviation 235.7 |
Secondary
Cumulative Amount of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48)
Time frame: Urine samples are collected: Day1 to 6.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Edaravone Oral Suspension | Cumulative Amount of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48) | Unchanged edaravone | 0.66 mg | Standard Deviation 0.21 |
| Edaravone Oral Suspension | Cumulative Amount of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48) | Sulfate conjugate | 10.04 mg | Standard Deviation 8.67 |
| Edaravone Oral Suspension | Cumulative Amount of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48) | Glucuronide Conjugate | 125.9 mg | Standard Deviation 19 |
| Edaravone IV Formulation | Cumulative Amount of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48) | Unchanged edaravone | 0.52 mg | Standard Deviation 0.15 |
| Edaravone IV Formulation | Cumulative Amount of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48) | Sulfate conjugate | 7.06 mg | Standard Deviation 6.43 |
| Edaravone IV Formulation | Cumulative Amount of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48) | Glucuronide Conjugate | 94.3 mg | Standard Deviation 13.7 |
Secondary
Cumulative Percentage of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48)
Time frame: Urine samples are collected: Day1 to 6.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Edaravone Oral Suspension | Cumulative Percentage of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48) | Unchanged edaravone | 0.629 percentage of dose | Standard Deviation 0.199 |
| Edaravone Oral Suspension | Cumulative Percentage of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48) | Sulfate conjugate | 6.58 percentage of dose | Standard Deviation 5.68 |
| Edaravone Oral Suspension | Cumulative Percentage of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48) | Glucuronide Conjugate | 59.8 percentage of dose | Standard Deviation 9 |
| Edaravone IV Formulation | Cumulative Percentage of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48) | Unchanged edaravone | 0.869 percentage of dose | Standard Deviation 0.252 |
| Edaravone IV Formulation | Cumulative Percentage of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48) | Sulfate conjugate | 8.09 percentage of dose | Standard Deviation 7.37 |
| Edaravone IV Formulation | Cumulative Percentage of Drug Excreted in Urine From Time Zero up to 48 Hours (Ae0-48) | Glucuronide Conjugate | 78.4 percentage of dose | Standard Deviation 11.4 |
Secondary
Elimination Rate Constant From the Central Compartment (Kel)
Time frame: The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Edaravone Oral Suspension | Elimination Rate Constant From the Central Compartment (Kel) | Unchanged edaravone | 0.1194 1/h | Standard Deviation 0.0876 |
| Edaravone Oral Suspension | Elimination Rate Constant From the Central Compartment (Kel) | Sulfate conjugate | 0.1295 1/h | Standard Deviation 0.0318 |
| Edaravone Oral Suspension | Elimination Rate Constant From the Central Compartment (Kel) | Glucuronide Conjugate | 0.1909 1/h | Standard Deviation 0.0417 |
| Edaravone IV Formulation | Elimination Rate Constant From the Central Compartment (Kel) | Unchanged edaravone | 0.1156 1/h | Standard Deviation 0.0563 |
| Edaravone IV Formulation | Elimination Rate Constant From the Central Compartment (Kel) | Sulfate conjugate | 0.1010 1/h | Standard Deviation 0.0324 |
| Edaravone IV Formulation | Elimination Rate Constant From the Central Compartment (Kel) | Glucuronide Conjugate | 0.1924 1/h | Standard Deviation 0.038 |
Secondary
Mean Residence Time From Time Zero up to Infinity With Extrapolation of the Terminal Phase (MRT0-inf) of Unchanged Edaravone
Time frame: The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Edaravone Oral Suspension | Mean Residence Time From Time Zero up to Infinity With Extrapolation of the Terminal Phase (MRT0-inf) of Unchanged Edaravone | 2.495 h | Standard Deviation 0.903 |
| Edaravone IV Formulation | Mean Residence Time From Time Zero up to Infinity With Extrapolation of the Terminal Phase (MRT0-inf) of Unchanged Edaravone | 2.333 h | Standard Deviation 0.826 |
Secondary
Number of Participants With Adverse Events and Adverse Drug Reactions
Time frame: Day 1 to 11
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Edaravone Oral Suspension | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 1 Participants |
| Edaravone Oral Suspension | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 0 Participants |
| Edaravone IV Formulation | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 1 Participants |
| Edaravone IV Formulation | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 0 Participants |
Secondary
Renal Clearance (CLr) of Unchanged Edaravone
Time frame: Urine samples are collected: Day1 to 6.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Edaravone Oral Suspension | Renal Clearance (CLr) of Unchanged Edaravone | 0.424 L/h | Standard Deviation 0.227 |
| Edaravone IV Formulation | Renal Clearance (CLr) of Unchanged Edaravone | 0.311 L/h | Standard Deviation 0.114 |
Secondary
Terminal Elimination Half-life (t1/2)
Time frame: The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Edaravone Oral Suspension | Terminal Elimination Half-life (t1/2) | Unchanged edaravone | 9.75 h | Standard Deviation 8.47 |
| Edaravone Oral Suspension | Terminal Elimination Half-life (t1/2) | Sulfate conjugate | 5.77 h | Standard Deviation 1.85 |
| Edaravone Oral Suspension | Terminal Elimination Half-life (t1/2) | Glucuronide Conjugate | 3.75 h | Standard Deviation 0.55 |
| Edaravone IV Formulation | Terminal Elimination Half-life (t1/2) | Unchanged edaravone | 8.82 h | Standard Deviation 8.33 |
| Edaravone IV Formulation | Terminal Elimination Half-life (t1/2) | Sulfate conjugate | 7.58 h | Standard Deviation 2.39 |
| Edaravone IV Formulation | Terminal Elimination Half-life (t1/2) | Glucuronide Conjugate | 3.69 h | Standard Deviation 0.48 |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax)
Time frame: The date of dosing is defined as Day 1. PO: Day 1 at pre-dose, 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 hrs; IV: Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Both groups: Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Edaravone Oral Suspension | Time to Reach Maximum Plasma Concentration (Tmax) | Unchanged edaravone | 0.50 h |
| Edaravone Oral Suspension | Time to Reach Maximum Plasma Concentration (Tmax) | Sulfate conjugate | 0.75 h |
| Edaravone Oral Suspension | Time to Reach Maximum Plasma Concentration (Tmax) | Glucuronide Conjugate | 0.75 h |
| Edaravone IV Formulation | Time to Reach Maximum Plasma Concentration (Tmax) | Unchanged edaravone | 1.00 h |
| Edaravone IV Formulation | Time to Reach Maximum Plasma Concentration (Tmax) | Sulfate conjugate | 1.08 h |
| Edaravone IV Formulation | Time to Reach Maximum Plasma Concentration (Tmax) | Glucuronide Conjugate | 1.08 h |
Secondary
Total Clearance (CL) of Unchanged Edaravone After Intravenous Administration
Time frame: The date of dosing is defined as Day 1. Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Edaravone Oral Suspension | Total Clearance (CL) of Unchanged Edaravone After Intravenous Administration | 35.9 L/h | Standard Deviation 7.5 |
Secondary
Volume of Distribution at Steady State (Vss) of Unchanged Edaravone After Intravenous Administration
Time frame: The date of dosing is defined as Day 1. Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Edaravone Oral Suspension | Volume of Distribution at Steady State (Vss) of Unchanged Edaravone After Intravenous Administration | 63.1 L | Standard Deviation 22 |
Secondary
Volume of Distribution During Terminal Phase (Vz) of Unchanged Edaravone After Intravenous Administration
Time frame: The date of dosing is defined as Day 1. Day 1 at pre-dose, 0.25, 0.5, 1, 1.083, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12 hrs; Day 2 at 24, 36 hrs; Day 3 at 48 hrs.
Population: This study was designed as a 2-group, 2-period crossover study with the advance administration of edaravone oral suspension group (PO =\> IV) with 21 subjects, and the advance administration of edaravone IV formulation group (IV =\> PO) with 21 subjects to investigate the bioequivalence between edaravone oral suspension and edaravone IV formulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Edaravone Oral Suspension | Volume of Distribution During Terminal Phase (Vz) of Unchanged Edaravone After Intravenous Administration | 418 L | Standard Deviation 321 |