Healthy Adult Subjects
Conditions
Brief summary
* Cohort 1: To evaluate the drug interactions, safety, and tolerability of oral edaravone when coadministered with rosuvastatin, sildenafil or furosemide in healthy adult males * Cohort 2: To evaluate the pharmacokinetics, safety, and tolerability of oral edaravone in healthy Japanese and Caucasian adult males
Interventions
Sponsors
Shionogi
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Intervention model description
Cohort 1 is open-label, non-randomized, sequential, and add-on study. Cohort 2 is single-dose, open-label, randomized, and cross-over study.
Eligibility
Sex/Gender
MALE
Age
20 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy adult male volunteers * Cohort 1: Japanese, Cohort 2: Japanese or Caucasian * 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 * Subjects who do not agree to use an effective method of contraception from initiation of study drug administration to 14 days after completion (discontinuation) of study drug administration * Subjects who have previously received edaravone * Subjects who have participated in another clinical study and received a study drug within 12 weeks before providing informed consent * Use of any drug(s) other than the study drug or as-needed use of acetylsalicylic acid within 7 days before the initiation of study drug or victim drug administration * Use of any alcohol, xanthine, or caffeine-containing product(s) within 24 hours before screening and Day -1 visiting * Use of any supplement(s) within 7 days before the initiation of study drug or victim drug administration * Use of grapefruit, grapefruit juice, or any processed food(s) containing these substances during the following periods (Cohort 1: within 7 days before the initiation of victim drug administration, Cohort 2: within 24 hours before each Day -1 visiting) * Use of any tobacco or nicotine-containing product(s) (Cohort 1: within 12 weeks before the initiation of victim drug administration during the following periods, Cohort 2: within 24 hours before each Day -1 visiting) * Use of any health food(s) containing St John's Wort (Hypericum perforatum) within 2 weeks before the initiation of victim drug administration (only in Cohort 1)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Rosuvastatin, Sildenafil and Furosemide. | Before rosuvastatin dosing and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before sildenafil dosing and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before furosemide dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose |
| Maximum Plasma Concentration (Cmax) of Rosuvastatin, Sildenafil and Furosemide. | Before rosuvastatin dosing and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before sildenafil dosing and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before furosemide dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose |
| Tmax of Rosuvastatin, Sildenafil and Furosemide. | Before rosuvastatin dosing and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before sildenafil dosing and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before furosemide dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose |
| T1/2 of Rosuvastatin, Sildenafil and Furosemide. | Before rosuvastatin dosing and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before sildenafil dosing and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before furosemide dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose |
| AUC0-inf of Unchanged Edaravone. | Group 1 (Day 6, 9 and 12) and Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose. |
| Cmax of Unchanged Edaravone. | Group 1 (Day 6, 9 and 12) and Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose. |
| Tmax of Unchanged Edaravone. | Group 1 (Day 6, 9 and 12) and Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose. |
| T1/2 of Unchanged Edaravone. | Group 1 (Day 6, 9 and 12) and Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose. |
| AUC0-inf of Sulfate Conjugate. | Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose. |
| Cmax of Sulfate Conjugate. | Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose. |
| Tmax of Sulfate Conjugate. | Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose. |
| T1/2 of Sulfate Conjugate. | Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose. |
| AUC0-inf of Glucuronide Conjugate. | Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose. |
| Cmax of Glucuronide Conjugate. | Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose. |
| Tmax of Glucuronide Conjugate. | Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose. |
| T1/2 of Glucuronide Conjugate. | Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose. |
| AUCinf of Sulfate Conjugate and Glucuronide Conjugate. | Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose |
| Cmax of Sulfate Conjugate and Glucuronide Conjugate. | Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose |
| Tmax of Sulfate Conjugate and Glucuronide Conjugate. | Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose |
| T1/2 of Sulfate Conjugate and Glucuronide Conjugate. | Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose |
| Number of Participants With Adverse Events and Adverse Drug Reactions | Day 1 to 20 in group 1 of cohort 1, Day 1 to 14 in group 2 of cohort 1, Day 1 to 14 of cohort 2 |
Secondary
| Measure | Time frame |
|---|---|
| AUCinf of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate. | Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose |
| Cmax of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate. | Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose |
| Tmax of Unchanged Edaravone. | Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose |
| T1/2 of Unchanged Edaravone. | Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose |
Countries
Japan
Contacts
STUDY_DIRECTORShionogi Clinical Trials Administrator Clinical Support Help Line
Shionogi
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rosuvastatin, Sildenafil, and Edaravone Group 1 of Cohort 1 A single-sequence study in which healthy male subjects receive a single dose of rosuvastatin on Day 1 followed by a single dose of sildenafil on Day 4. MT-1186 will be administered from Day 6 to 13 with co-administration of rosuvastatin and sildenafil on Day 9 and 12, respectively. | 32 |
| Furosemide and Edaravone Group 2 of Cohort 1 A single-sequence study in which healthy male subjects receive a single dose of furosemide on Day 1. MT-1186 will be administered from Day 3 to 7 with co-administration of furosemide on Day 6. | 34 |
| Japanese Combined of Cohort 2 A three-way crossover study in which Japanese healthy male subjects receive a single dose of MT-1186 under several dosing condition on Day 1, 4, and 7 according to their treatment sequence with 3-day wash out between doses. | 9 |
| Caucasian Group of Cohort 2 Caucasian healthy male subjects receive a single dose of MT-1186 under fasted condition at the same period with Japanese subjects on Day 1, 4, or 7 according to their treatment schedule. | 9 |
| Total | 84 |
Baseline characteristics
| Characteristic | Furosemide and Edaravone Group 2 of Cohort 1 | Japanese Combined of Cohort 2 | Rosuvastatin, Sildenafil, and Edaravone Group 1 of Cohort 1 | Caucasian Group of Cohort 2 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants | 9 Participants | 32 Participants | 9 Participants | 84 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 34 Participants | 9 Participants | 32 Participants | 0 Participants | 75 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 9 Participants | 9 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 34 Participants | 9 Participants | 32 Participants | 9 Participants | 84 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 31 | 0 / 31 | 0 / 31 | 0 / 31 | 0 / 31 | 0 / 34 | 0 / 34 | 0 / 34 | 0 / 34 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 0 / 32 | 2 / 31 | 0 / 31 | 6 / 31 | 3 / 31 | 8 / 31 | 1 / 34 | 0 / 34 | 7 / 34 | 7 / 34 | 0 / 9 | 2 / 9 | 0 / 9 | 0 / 9 |
| serious Total, serious adverse events | 0 / 32 | 0 / 31 | 0 / 31 | 0 / 31 | 0 / 31 | 0 / 31 | 0 / 34 | 0 / 34 | 0 / 34 | 0 / 34 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 |
Outcome results
Primary
Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Rosuvastatin, Sildenafil and Furosemide.
Time frame: Before rosuvastatin dosing and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before sildenafil dosing and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before furosemide dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Rosuvastatin, Sildenafil and Furosemide. | 161 ng*h/mL | Standard Deviation 66.8 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Rosuvastatin, Sildenafil and Furosemide. | 165 ng*h/mL | Standard Deviation 60.2 |
| Sildenafil Alone: Group 1 of Cohort 1 | Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Rosuvastatin, Sildenafil and Furosemide. | 532 ng*h/mL | Standard Deviation 236 |
| Sildenafil + Edaravone: Group 1 of Cohort 1 | Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Rosuvastatin, Sildenafil and Furosemide. | 482 ng*h/mL | Standard Deviation 195 |
| Furosemide Alone: Group 2 of Cohort 1 | Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Rosuvastatin, Sildenafil and Furosemide. | 3861 ng*h/mL | Standard Deviation 1031 |
| Furosemide + Edaravone: Group 2 of Cohort 1 | Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Rosuvastatin, Sildenafil and Furosemide. | 3906 ng*h/mL | Standard Deviation 736.2 |
Comparison: PK parameters of rosuvastatin, sildenafil, and furosemide alone and in the presence of edaravone were analyzed for the assessments of effect on PK of rosuvastatin, sildenafil, and furosemide by edaravone.90% CI: [0.97, 1.08]
Comparison: PK parameters of rosuvastatin, sildenafil, and furosemide alone and in the presence of edaravone were analyzed for the assessments of effect on PK of rosuvastatin, sildenafil, and furosemide by edaravone.90% CI: [0.88, 0.99]
Comparison: PK parameters of rosuvastatin, sildenafil, and furosemide alone and in the presence of edaravone were analyzed for the assessments of effect on PK of rosuvastatin, sildenafil, and furosemide by edaravone.90% CI: [0.98, 1.09]
Primary
AUC0-inf of Glucuronide Conjugate.
Time frame: Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose.
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2). Sulfate and glucuronide conjugates were not measured in Cohort 1 Group 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | AUC0-inf of Glucuronide Conjugate. | Day 3: Group 2 (Edaravone alone) | 4817 ng*h/mL | Standard Deviation 1282 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | AUC0-inf of Glucuronide Conjugate. | Day 6: Group 2 (Edaravone + Furosemide) | 4953 ng*h/mL | Standard Deviation 1285 |
Primary
AUC0-inf of Sulfate Conjugate.
Time frame: Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose.
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2). Sulfate and glucuronide conjugates were not measured in Cohort 1 Group 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | AUC0-inf of Sulfate Conjugate. | Day 3: Group 2 (Edaravone alone) | 26576 ng*h/mL | Standard Deviation 6820 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | AUC0-inf of Sulfate Conjugate. | Day 6: Group 2 (Edaravone + Furosemide) | 30588 ng*h/mL | Standard Deviation 7064 |
Primary
AUC0-inf of Unchanged Edaravone.
Time frame: Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. Three groups of randomized Japanese subjects received a single dose of edaravone under each of 3 dosing meal conditions in a 3-way, 3-period crossover fashion (3X3) in Cohort 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | AUC0-inf of Unchanged Edaravone. | 1647 ng*h/mL | Standard Deviation 433 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | AUC0-inf of Unchanged Edaravone. | 1475 ng*h/mL | Standard Deviation 658 |
| Sildenafil Alone: Group 1 of Cohort 1 | AUC0-inf of Unchanged Edaravone. | 1247 ng*h/mL | Standard Deviation 425 |
Comparison: PK parameters of unchanged edaravone were analyzed for the assessments of food effect on PK.90% CI: [0.697, 1.017]
Comparison: PK parameters of unchanged edaravone were analyzed for the assessments of food effect on PK.90% CI: [0.61, 0.891]
Primary
AUC0-inf of Unchanged Edaravone.
Time frame: Group 1 (Day 6, 9 and 12) and Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose.
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2). Day 3 of Group 1 and Day 9 and 12 of Group 2 were zero participant because no data was collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | AUC0-inf of Unchanged Edaravone. | Day 6: Group 1 (Edaravpne alone), Group 2 (Edaravone + Furosemide) | 2616 ng*h/mL | Standard Deviation 730 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | AUC0-inf of Unchanged Edaravone. | Day 9: Group 1 (Edaravone + Rosuvastatin), Group 2 Not Applicable | 2591 ng*h/mL | Standard Deviation 671 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | AUC0-inf of Unchanged Edaravone. | Day 12: Group 1 (Edaravone + Sildenafil), Group 2 Not Applicable | 2656 ng*h/mL | Standard Deviation 712 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | AUC0-inf of Unchanged Edaravone. | Day 3: Group 2 (Edaravone alone) | 2535 ng*h/mL | Standard Deviation 919 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | AUC0-inf of Unchanged Edaravone. | Day 6: Group 1 (Edaravpne alone), Group 2 (Edaravone + Furosemide) | 2746 ng*h/mL | Standard Deviation 1015 |
Primary
AUCinf of Sulfate Conjugate and Glucuronide Conjugate.
Time frame: Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. Three groups of randomized Japanese subjects received a single dose of edaravone under each of 3 dosing meal conditions in a 3-way, 3-period crossover fashion (3X3) in Cohort 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | AUCinf of Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 24484 ng*h/mL | Standard Deviation 5861 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | AUCinf of Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 4178 ng*h/mL | Standard Deviation 873 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | AUCinf of Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 22689 ng*h/mL | Standard Deviation 6334 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | AUCinf of Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 4099 ng*h/mL | Standard Deviation 637 |
| Sildenafil Alone: Group 1 of Cohort 1 | AUCinf of Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 23022 ng*h/mL | Standard Deviation 5094 |
| Sildenafil Alone: Group 1 of Cohort 1 | AUCinf of Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 3557 ng*h/mL | Standard Deviation 879 |
Primary
Cmax of Glucuronide Conjugate.
Time frame: Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose.
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2). Sulfate and glucuronide conjugates were not measured in Cohort 1 Group 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Cmax of Glucuronide Conjugate. | Day 3: Group 2 (Edaravone alone) | 2318 ng/mL | Standard Deviation 649 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Cmax of Glucuronide Conjugate. | Day 6: Group 2 (Edaravone + Furosemide) | 2304 ng/mL | Standard Deviation 694 |
Primary
Cmax of Sulfate Conjugate.
Time frame: Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose.
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2). Sulfate and glucuronide conjugates were not measured in Cohort 1 Group 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Cmax of Sulfate Conjugate. | Day 3: Group 2 (Edaravone alone) | 8115 ng/mL | Standard Deviation 1775 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Cmax of Sulfate Conjugate. | Day 6: Group 2 (Edaravone + Furosemide) | 8702 ng/mL | Standard Deviation 2147 |
Primary
Cmax of Sulfate Conjugate and Glucuronide Conjugate.
Time frame: Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. Three groups of randomized Japanese subjects received a single dose of edaravone under each of 3 dosing meal conditions in a 3-way, 3-period crossover fashion (3X3) in Cohort 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Cmax of Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 8394 ng/mL | Standard Deviation 1609 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Cmax of Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 2391 ng/mL | Standard Deviation 508 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Cmax of Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 7802 ng/mL | Standard Deviation 1556 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Cmax of Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 2176 ng/mL | Standard Deviation 475 |
| Sildenafil Alone: Group 1 of Cohort 1 | Cmax of Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 8152 ng/mL | Standard Deviation 1731 |
| Sildenafil Alone: Group 1 of Cohort 1 | Cmax of Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 1924 ng/mL | Standard Deviation 380 |
Primary
Cmax of Unchanged Edaravone.
Time frame: Group 1 (Day 6, 9 and 12) and Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose.
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2). Day 3 of Group 1 and Day 9 and 12 of Group 2 were zero participant because no data was collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Cmax of Unchanged Edaravone. | Day 6: Group 1 (Edaravpne alone), Group 2 (Edaravone + Furosemide) | 2724 ng/mL | Standard Deviation 1533 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Cmax of Unchanged Edaravone. | Day 9: Group 1 (Edaravone + Rosuvastatin) | 2302 ng/mL | Standard Deviation 943 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Cmax of Unchanged Edaravone. | Day 12: Group 1 (Edaravone + Sildenafil) | 2455 ng/mL | Standard Deviation 1111 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Cmax of Unchanged Edaravone. | Day 3: Group 2 (Edaravone alone) | 2180 ng/mL | Standard Deviation 1035 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Cmax of Unchanged Edaravone. | Day 6: Group 1 (Edaravpne alone), Group 2 (Edaravone + Furosemide) | 2074 ng/mL | Standard Deviation 1051 |
Primary
Cmax of Unchanged Edaravone.
Time frame: Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. Three groups of randomized Japanese subjects received a single dose of edaravone under each of 3 dosing meal conditions in a 3-way, 3-period crossover fashion (3X3) in Cohort 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Cmax of Unchanged Edaravone. | 1810 ng/mL | Standard Deviation 849.8 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Cmax of Unchanged Edaravone. | 1502 ng/mL | Standard Deviation 1272 |
| Sildenafil Alone: Group 1 of Cohort 1 | Cmax of Unchanged Edaravone. | 1012 ng/mL | Standard Deviation 603.3 |
Comparison: PK parameters of unchanged edaravone were analyzed for the assessments of food effect on PK.90% CI: [0.379, 1.137]
Comparison: PK parameters of unchanged edaravone were analyzed for the assessments of food effect on PK.90% CI: [0.301, 0.903]
Primary
Maximum Plasma Concentration (Cmax) of Rosuvastatin, Sildenafil and Furosemide.
Time frame: Before rosuvastatin dosing and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before sildenafil dosing and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before furosemide dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Maximum Plasma Concentration (Cmax) of Rosuvastatin, Sildenafil and Furosemide. | 11.3 ng/mL | Standard Deviation 5 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Maximum Plasma Concentration (Cmax) of Rosuvastatin, Sildenafil and Furosemide. | 11.3 ng/mL | Standard Deviation 5 |
| Sildenafil Alone: Group 1 of Cohort 1 | Maximum Plasma Concentration (Cmax) of Rosuvastatin, Sildenafil and Furosemide. | 232 ng/mL | Standard Deviation 135 |
| Sildenafil + Edaravone: Group 1 of Cohort 1 | Maximum Plasma Concentration (Cmax) of Rosuvastatin, Sildenafil and Furosemide. | 201 ng/mL | Standard Deviation 97.9 |
| Furosemide Alone: Group 2 of Cohort 1 | Maximum Plasma Concentration (Cmax) of Rosuvastatin, Sildenafil and Furosemide. | 1676 ng/mL | Standard Deviation 777.7 |
| Furosemide + Edaravone: Group 2 of Cohort 1 | Maximum Plasma Concentration (Cmax) of Rosuvastatin, Sildenafil and Furosemide. | 1701 ng/mL | Standard Deviation 506.5 |
Comparison: PK parameters of rosuvastatin, sildenafil, and furosemide alone and in the presence of edaravone were analyzed for the assessments of effect on PK of rosuvastatin, sildenafil, and furosemide by edaravone.90% CI: [0.91, 1.06]
Comparison: PK parameters of rosuvastatin, sildenafil, and furosemide alone and in the presence of edaravone were analyzed for the assessments of effect on PK of rosuvastatin, sildenafil, and furosemide by edaravone.90% CI: [0.8, 1.1]
Comparison: PK parameters of rosuvastatin, sildenafil, and furosemide alone and in the presence of edaravone were analyzed for the assessments of effect on PK of rosuvastatin, sildenafil, and furosemide by edaravone.90% CI: [0.96, 1.23]
Primary
Number of Participants With Adverse Events and Adverse Drug Reactions
Time frame: Day 1 to 20 in group 1 of cohort 1, Day 1 to 14 in group 2 of cohort 1, Day 1 to 14 of cohort 2
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. Three groups of randomized Japanese subjects received a single dose of edaravone under each of 3 dosing meal conditions in a 3-way, 3-period crossover fashion (3X3) in Cohort 2.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 0 Participants |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 0 Participants |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 2 Participants |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 0 Participants |
| Sildenafil Alone: Group 1 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 0 Participants |
| Sildenafil Alone: Group 1 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 0 Participants |
| Sildenafil + Edaravone: Group 1 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 6 Participants |
| Sildenafil + Edaravone: Group 1 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 5 Participants |
| Furosemide Alone: Group 2 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 0 Participants |
| Furosemide Alone: Group 2 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 3 Participants |
| Furosemide + Edaravone: Group 2 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 5 Participants |
| Furosemide + Edaravone: Group 2 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 8 Participants |
| Furosemide Alone: Group 2 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 1 Participants |
| Furosemide Alone: Group 2 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 0 Participants |
| Edaravone Alone: Group 2 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 0 Participants |
| Edaravone Alone: Group 2 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 0 Participants |
| Edaravone + Furosemide: Group 2 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 0 Participants |
| Edaravone + Furosemide: Group 2 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 7 Participants |
| Combined : After Day 3: Group 2 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 0 Participants |
| Combined : After Day 3: Group 2 of Cohort 1 | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 7 Participants |
| Edaravone Single Dose Under Fasting Condition: Japanese Conmibed | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 0 Participants |
| Edaravone Single Dose Under Fasting Condition: Japanese Conmibed | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 0 Participants |
| Edaravone Single Dose 1 Hour After a High-fat Meal: Japanese Conmibed | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 1 Participants |
| Edaravone Single Dose 1 Hour After a High-fat Meal: Japanese Conmibed | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 2 Participants |
| Edaravone Single Dose 4 Hours After a High-fat Meal: Japanese Conmibed | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 0 Participants |
| Edaravone Single Dose 4 Hours After a High-fat Meal: Japanese Conmibed | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 0 Participants |
| Edaravone Single Dose Under Fasting Condition: White Conbined | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with adverse drug reactions | 0 Participants |
| Edaravone Single Dose Under Fasting Condition: White Conbined | Number of Participants With Adverse Events and Adverse Drug Reactions | Number of Participants with Adverse events | 0 Participants |
Primary
T1/2 of Glucuronide Conjugate.
Time frame: Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose.
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2). Sulfate and glucuronide conjugates were not measured in Cohort 1 Group 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Glucuronide Conjugate. | Day 3: Group 2 (Edaravone alone) | 3.65 h | Standard Deviation 0.28 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Glucuronide Conjugate. | Day 6: Group 2 (Edaravone + Furosemide) | 3.97 h | Standard Deviation 0.31 |
Primary
T1/2 of Glucuronide Conjugate.
Time frame: Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Glucuronide Conjugate. | 4.26 h | Standard Deviation 0.38 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | T1/2 of Glucuronide Conjugate. | 4.35 h | Standard Deviation 0.25 |
Primary
T1/2 of Rosuvastatin, Sildenafil and Furosemide.
Time frame: Before rosuvastatin dosing and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before sildenafil dosing and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before furosemide dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Rosuvastatin, Sildenafil and Furosemide. | 14.4 h | Standard Deviation 4 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | T1/2 of Rosuvastatin, Sildenafil and Furosemide. | 12.1 h | Standard Deviation 2.2 |
| Sildenafil Alone: Group 1 of Cohort 1 | T1/2 of Rosuvastatin, Sildenafil and Furosemide. | 2.8 h | Standard Deviation 1.1 |
| Sildenafil + Edaravone: Group 1 of Cohort 1 | T1/2 of Rosuvastatin, Sildenafil and Furosemide. | 3.5 h | Standard Deviation 1.4 |
| Furosemide Alone: Group 2 of Cohort 1 | T1/2 of Rosuvastatin, Sildenafil and Furosemide. | 6.9 h | Standard Deviation 3.5 |
| Furosemide + Edaravone: Group 2 of Cohort 1 | T1/2 of Rosuvastatin, Sildenafil and Furosemide. | 5.8 h | Standard Deviation 3.8 |
Primary
T1/2 of Sulfate Conjugate.
Time frame: Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose.
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2). Sulfate and glucuronide conjugates were not measured in Cohort 1 Group 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Sulfate Conjugate. | Day 3: Group 2 (Edaravone alone) | 3.89 h | Standard Deviation 0.25 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Sulfate Conjugate. | Day 6: Group 2 (Edaravone + Furosemide) | 4.20 h | Standard Deviation 0.33 |
Primary
T1/2 of Sulfate Conjugate and Glucuronide Conjugate.
Time frame: Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. Three groups of randomized Japanese subjects received a single dose of edaravone under each of 3 dosing meal conditions in a 3-way, 3-period crossover fashion (3X3) in Cohort 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 10.50 h | Standard Deviation 7.67 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 4.26 h | Standard Deviation 0.38 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | T1/2 of Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 7.53 h | Standard Deviation 3.55 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | T1/2 of Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 3.89 h | Standard Deviation 0.79 |
| Sildenafil Alone: Group 1 of Cohort 1 | T1/2 of Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 7.55 h | Standard Deviation 2.47 |
| Sildenafil Alone: Group 1 of Cohort 1 | T1/2 of Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 3.88 h | Standard Deviation 0.55 |
Primary
T1/2 of Unchanged Edaravone.
Time frame: Group 1 (Day 6, 9 and 12) and Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose.
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2).~Day 3 of Group 1 and Day 9 and 12 of Group 2 were zero participants because no data was collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Unchanged Edaravone. | Day 6: Group 1 (Edaravpne alone), Group 2 (Edaravone + Furosemide) | 5.23 h | Standard Deviation 1.11 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Unchanged Edaravone. | Day 9: Group 1 (Edaravone + Rosuvastatin) | 6.60 h | Standard Deviation 1.18 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Unchanged Edaravone. | Day 12: Group 1 (Edaravone + Sildenafil) | 6.69 h | Standard Deviation 1.31 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | T1/2 of Unchanged Edaravone. | Day 3: Group 2 (Edaravone alone) | 4.67 h | Standard Deviation 0.92 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | T1/2 of Unchanged Edaravone. | Day 6: Group 1 (Edaravpne alone), Group 2 (Edaravone + Furosemide) | 5.52 h | Standard Deviation 0.6 |
Primary
T1/2 of Unchanged Edaravone.
Time frame: Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. Three groups of randomized Japanese subjects received a single dose of edaravone under each of 3 dosing meal conditions in a 3-way, 3-period crossover fashion (3X3) in Cohort 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Unchanged Edaravone. | 9.33 h | Standard Deviation 4.87 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | T1/2 of Unchanged Edaravone. | 9.65 h | Standard Deviation 5.41 |
| Sildenafil Alone: Group 1 of Cohort 1 | T1/2 of Unchanged Edaravone. | 7.66 h | Standard Deviation 4.12 |
Primary
Tmax of Glucuronide Conjugate.
Time frame: Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose.
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2). Sulfate and glucuronide conjugates were not measured in Cohort 1 Group 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Tmax of Glucuronide Conjugate. | Day 3: Group 2 (Edaravone alone) | 0.61 h | Standard Deviation 0.26 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Tmax of Glucuronide Conjugate. | Day 6: Group 2 (Edaravone + Furosemide) | 0.57 h | Standard Deviation 0.18 |
Primary
Tmax of Rosuvastatin, Sildenafil and Furosemide.
Time frame: Before rosuvastatin dosing and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before sildenafil dosing and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose, Before furosemide dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hrs post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Tmax of Rosuvastatin, Sildenafil and Furosemide. | 4.6 h | Standard Deviation 1.5 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Tmax of Rosuvastatin, Sildenafil and Furosemide. | 5.1 h | Standard Deviation 1.4 |
| Sildenafil Alone: Group 1 of Cohort 1 | Tmax of Rosuvastatin, Sildenafil and Furosemide. | 0.8 h | Standard Deviation 0.4 |
| Sildenafil + Edaravone: Group 1 of Cohort 1 | Tmax of Rosuvastatin, Sildenafil and Furosemide. | 0.9 h | Standard Deviation 0.5 |
| Furosemide Alone: Group 2 of Cohort 1 | Tmax of Rosuvastatin, Sildenafil and Furosemide. | 1.7 h | Standard Deviation 1.1 |
| Furosemide + Edaravone: Group 2 of Cohort 1 | Tmax of Rosuvastatin, Sildenafil and Furosemide. | 1.8 h | Standard Deviation 1.1 |
Primary
Tmax of Sulfate Conjugate.
Time frame: Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose.
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2). Sulfate and glucuronide conjugates were not measured in Cohort 1 Group 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Tmax of Sulfate Conjugate. | Day 3: Group 2 (Edaravone alone) | 0.76 h | Standard Deviation 0.28 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Tmax of Sulfate Conjugate. | Day 6: Group 2 (Edaravone + Furosemide) | 0.81 h | Standard Deviation 0.3 |
Primary
Tmax of Sulfate Conjugate and Glucuronide Conjugate.
Time frame: Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. Three groups of randomized Japanese subjects received a single dose of edaravone under each of 3 dosing meal conditions in a 3-way, 3-period crossover fashion (3X3) in Cohort 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Tmax of Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 0.67 h | Standard Deviation 0.25 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Tmax of Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 0.53 h | Standard Deviation 0.2 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Tmax of Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 0.91 h | Standard Deviation 0.39 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Tmax of Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 0.76 h | Standard Deviation 0.35 |
| Sildenafil Alone: Group 1 of Cohort 1 | Tmax of Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 0.72 h | Standard Deviation 0.26 |
| Sildenafil Alone: Group 1 of Cohort 1 | Tmax of Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 0.72 h | Standard Deviation 0.26 |
Primary
Tmax of Unchanged Edaravone.
Time frame: Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. Three groups of randomized Japanese subjects received a single dose of edaravone under each of 3 dosing meal conditions in a 3-way, 3-period crossover fashion (3X3) in Cohort 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Tmax of Unchanged Edaravone. | 0.25 h |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Tmax of Unchanged Edaravone. | 0.50 h |
| Sildenafil Alone: Group 1 of Cohort 1 | Tmax of Unchanged Edaravone. | 0.25 h |
Primary
Tmax of Unchanged Edaravone.
Time frame: Group 1 (Day 6, 9 and 12) and Group 2 (Day 3 and 6): Pre-dose, 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours post-dose.
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone.~DDI effects of oral edaravone was evaluated based on the number of subjects in each period in Cohort 1 (Group 1: Period 1 to 3, Group 2: Period 1 and 2).~Day 3 of Group 1 and Day 9 and 12 of Group 2 were zero participants because no data was collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Tmax of Unchanged Edaravone. | Day 6: Group 1 (Edaravpne alone), Group 2 (Edaravone + Furosemide) | 0.30 h | Standard Deviation 0.1 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Tmax of Unchanged Edaravone. | Day 9: Group 1 (Edaravone + Rosuvastatin) | 0.34 h | Standard Deviation 0.13 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Tmax of Unchanged Edaravone. | Day 12: Group 1 (Edaravone + Sildenafil) | 0.32 h | Standard Deviation 0.17 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Tmax of Unchanged Edaravone. | Day 3: Group 2 (Edaravone alone) | 0.34 h | Standard Deviation 0.19 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Tmax of Unchanged Edaravone. | Day 6: Group 1 (Edaravpne alone), Group 2 (Edaravone + Furosemide) | 0.34 h | Standard Deviation 0.17 |
Secondary
AUCinf of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate.
Time frame: Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. 18 subjects (9 Japanese and 9 White) were enrolled in Cohort 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | AUCinf of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate. | Unchanged edaravone | 1647 ng*h/mL | Standard Deviation 433 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | AUCinf of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 24484 ng*h/mL | Standard Deviation 5861 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | AUCinf of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 4178 ng*h/mL | Standard Deviation 873 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | AUCinf of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate. | Unchanged edaravone | 1423 ng*h/mL | Standard Deviation 391 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | AUCinf of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 20098 ng*h/mL | Standard Deviation 1592 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | AUCinf of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 3795 ng*h/mL | Standard Deviation 571 |
Secondary
Cmax of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate.
Time frame: Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. 18 subjects (9 Japanese and 9 White) were enrolled in Cohort 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Cmax of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate. | Unchanged edaravone | 1810 ng/mL | Standard Deviation 850 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Cmax of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 8394 ng/mL | Standard Deviation 1609 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Cmax of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 2391 ng/mL | Standard Deviation 508 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Cmax of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate. | Unchanged edaravone | 1484 ng/mL | Standard Deviation 920 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Cmax of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate. | Sulfate conjugate | 6530 ng/mL | Standard Deviation 787 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Cmax of Unchanged Edaravone, Sulfate Conjugate and Glucuronide Conjugate. | Glucuronide conjugate | 2136 ng/mL | Standard Deviation 403 |
Secondary
T1/2 of Unchanged Edaravone.
Time frame: Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. 18 subjects (9 Japanese and 9 White) were enrolled in Cohort 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Unchanged Edaravone. | Unchanged edaravone | 9.3 h | Standard Deviation 4.9 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Unchanged Edaravone. | Sulfate conjugate | 10.5 h | Standard Deviation 7.7 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | T1/2 of Unchanged Edaravone. | Glucuronide conjugate | 4.3 h | Standard Deviation 0.4 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | T1/2 of Unchanged Edaravone. | Unchanged edaravone | 16.2 h | Standard Deviation 15.8 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | T1/2 of Unchanged Edaravone. | Sulfate conjugate | 10.7 h | Standard Deviation 6.5 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | T1/2 of Unchanged Edaravone. | Glucuronide conjugate | 4.4 h | Standard Deviation 0.3 |
Secondary
Tmax of Unchanged Edaravone.
Time frame: Before dosing, and 0.083, 0.25, 0.5 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose
Population: This study was conducted in 2 cohorts; the first cohort assessed DDIs with multiple doses of oral edaravone, and the second cohort evaluated PK and racial differences in PK parameters with oral administration of edaravone. 18 subjects (9 Japanese and 9 White) were enrolled in Cohort 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin Alone: Group 1 of Cohort 1 | Tmax of Unchanged Edaravone. | Unchanged edaravone | 0.4 h | Standard Deviation 0.3 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Tmax of Unchanged Edaravone. | Sulfate conjugate | 0.67 h | Standard Deviation 0.25 |
| Rosuvastatin Alone: Group 1 of Cohort 1 | Tmax of Unchanged Edaravone. | Glucuronide conjugate | 0.53 h | Standard Deviation 0.2 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Tmax of Unchanged Edaravone. | Unchanged edaravone | 0.4 h | Standard Deviation 0.2 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Tmax of Unchanged Edaravone. | Sulfate conjugate | 0.67 h | Standard Deviation 0.25 |
| Rosubastatin + Edaravone: Group 1 of Cohort 1 | Tmax of Unchanged Edaravone. | Glucuronide conjugate | 0.61 h | Standard Deviation 0.22 |