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The purpose of this study is to evaluate how much of the investigational product gets into the blood stream and how long the body takes to get rid of it when given to subjects with a range of liver impairment compared to subjects with normal liver function.
This is a multi-center, open-label, parallel-arm study in 1 group of subjects with normal hepatic function and 3 groups of subjects with varying degrees of hepatic impairment (mild, moderate, and severe). Subjects will be confined to the clinic from Day -1 to Day 8. Subjects will be contacted via telephone 30 days (+ 2 days) after the last dose of study medication to assess any new or ongoing AEs and to record concomitant medications. All groups will receive a single oral 2-mg OPC-34712 dose on Day 1 with 240 mL room temperature still water. Subjects will be administered the OPC-34712 dose in the fasted state (at least 8 hours of fasting) and no food will be allowed for 4 hours postdose.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Normal | Active Comparator |
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| Mild | Active Comparator |
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| Moderate | Active Comparator |
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| Severe | Active Comparator |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| OPC-34712 | Drug | All groups will receive a single oral 2-mg OPC-34712 dose on Day 1 with 240 mL room temperature still water. Subjects will be administered the OPC-34712 dose in the fasted state (at least 8 hours of fasting) and no food will be allowed for 4 hours postdose. Water will be restricted as part of the dosing procedure from 1 hour prior to dosing and 2 hours post-dose. |
| Measure | Description | Time Frame |
|---|---|---|
| Unbound Brexpiprazole Area Under the Concentration Time Curve (AUC) Calculated to the Last Observable Concentration at Time t (AUCt,u) | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/Early termination (ET). | Day 1 to Day 8 |
| Unbound Brexpiprazole AUC Calculated From Time Zero to Infinity (AUC∞,u) | Blood samples were taken at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. AUC (0 - ∞)= AUC from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). | Day 1 to Day 8 |
| Unbound Maximum Plasma Concentration of Brexpiprazole (Cmax,u) | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. Cmax,u is the highest measured unbound plasma concentration during the dosing interval. | Day 1 to Day 8 |
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Curve of Brexpiprazole Calculated to the Last Observable Concentration at Time t (AUCt) | Blood samples were taken at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. AUCt= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t) The AUCt was estimated using the linear trapezoidal rule. |
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Inclusion Criteria:
Inclusion Criteria for Hepatically Impaired Subjects Only:
Inclusion Criteria for Subjects with Normal Hepatic Function Only
Exclusion Criteria:
Exclusion Criteria for Hepatically Impaired Subjects Only:
Exclusion Criteria for Subjects with Normal Hepatic Function Only:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Study Site | Miami | Florida | 33014 | United States | ||
| Study Site |
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81 participants were screened; of these 45 participants were enrolled recruited at 3 study sites in the United States (US).
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| ID | Title | Description |
|---|---|---|
| FG000 | Mild Hepatic Impairment | Participants with mild hepatic impairment (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 milligrams (mg). |
| FG001 | Moderate Hepatic Impairment | Participants with moderate hepatic impairment (Child-Pugh classification scheme)received a single dose of oral brexpiprazole 2 mg. |
| FG002 | Severe Hepatic Impairment | Participants with severe hepatic impairment (based on Child-Pugh classification scheme) received a single dose of oral brexpiprazole 2 mg. |
| FG003 | Normal Hepatic Function | Participants with normal hepatic function (based on Child-Pugh classification scheme) received a single dose of oral brexpiprazole 2 mg. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Mild Hepatic Impairment | Participants with mild hepatic impairment (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 mg. |
| BG001 | Moderate Hepatic Impairment |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Unbound Brexpiprazole Area Under the Concentration Time Curve (AUC) Calculated to the Last Observable Concentration at Time t (AUCt,u) | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/Early termination (ET). | Pharmacokinetics (PK) set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | nanograms.hours/mL (ng*h/mL) | Day 1 to Day 8 |
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Adverse events were recorded from the time the Informed Consent Form was signed, throughout the 8 day study up to 30 days after study drug administration.
The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Mild Hepatic Impairment | Participants with mild hepatic impairment (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 mg. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Global Medical Affairs | Otsuka Pharmaceutical Development and Commercialization, Inc. | 800-562-3974 |
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| ID | Term |
|---|---|
| D012559 | Schizophrenia |
| ID | Term |
|---|---|
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D001523 | Mental Disorders |
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| Day 1 to Day 8 |
| Area Under the Concentration Time Curve of Brexpiprazole From Time Zero to Infinity (AUC∞) | Blood samples were taken at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. AUC (0 - ∞)= AUC from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). The AUC∞ was estimated using the linear trapezoidal rule | Day 1 to Day 8 |
| Maximum Plasma Concentration of Brexpiprazole (Cmax) | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. Cmax is the highest measured concentration of the drug during the dosing interval. Actual blood sample times were used for PK calculations. Values for Cmax and tmax were determined directly from the observed data. | Day 1 to Day 8 |
| Time to Cmax of Brexiprazole (Tmax) | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. Tmax is the time taken to reach highest measured concentration of the drug during the dosing interval. Actual blood sample times were used for PK calculations. Values for Cmax and tmax were determined directly from the observed data. | Day 1 to Day 8 |
| Apparent Clearance of Brexpiprazole From Plasma After Extravascular Administration (CL/F) | The value of CL/F (brexpiprazole only) was determined as Dose/AUC∞. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Day 1 to Day 8 |
| Unbound Fraction of Brexpiprazole in Plasma (fu) | Blood samples were taken at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. | Day 1 to Day 8 |
| Apparent Unbound Clearance of Brexpiprazole From Plasma After Extravascular Administration (CLu/F) | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. The value of CLu/F (brexpiprazole only) was determined as dose normalized unbound area under the concentration-time curve from time zero to infinity (Dose/AUC∞,u). | Day 1 to Day 8 |
| Terminal-phase Elimination Half-life of Brexpiprazole (t1/2,z) | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. The t1/2,z was determined as (ln2)/λz. Terminal-phase elimination half-life is the time measured for the plasma concentration to decrease by one half. | Day 1 to Day 8 |
| Renal Clearance (CLr) of Brexipiprazole | Urine samples were taken at pre-dose and during the following increments: 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours postdose. The value of CLr was calculated as Ae,u/AUCt. | Day 1 to Day 8 |
| Cumulative Amount of Brexpiprazole Excreted Into the Urine (Ae,u) | Urine samples were taken at pre-dose and during the following increments: 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours postdose. The value of Ae,u was calculated as the summation of urine concentration × urine volume from each collection interval | Day 1 to Day 8 |
| Fraction of Systemically Available Brexpiprazole Excreted Into the Urine (fe,u) | Urine samples were taken at pre-dose and during the following increments: 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours postdose.. The value of fe,u was calculated as 100 × Ae,u/Dose. | Day 1 to Day 8 |
| AUCt for DM-3411 Metabolite | Blood samples were taken at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. AUCt= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t) The AUCt was estimated using the linear trapezoidal rule. | Day 1 to Day 8 |
| AUC∞ for DM-3411 Metabolite | Blood samples were taken at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. The AUC∞ were estimated using the linear trapezoidal rule. | Day 1 to Day 8 |
| Cmax for DM-3411 Metabolite | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. Cmax is the highest measured concentration of the metabolite during the dosing interval. | Day 1 to Day 8 |
| Tmax for DM-3411 Metabolite | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. Tmax is the time taken to reach highest measured concentration of the metabolite during the dosing interval. | Day 1 to Day 8 |
| t1/2,z for DM-3411 Metabolite | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. The t1/2,z was determined as (ln2)/λz. | Day 1 to Day 8 |
| Ae,u for DM-3411 Metabolite | Urine samples were taken at pre-dose and during the following increments: 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours postdose. The value of Ae,u was calculated as the summation of urine concentration × urine volume from each collection interval. | Day 1 to Day 8 |
| fe,u for DM-3411 Metabolite | Urine samples were taken at pre-dose and during the following increments: 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours postdose. The value of fe,u was calculated as 100 × Ae,u/Dose. | Day 1 to Day 8 |
| CLr for DM-3411 Metabolite | Urine samples were taken at pre-dose and during the following increments: 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours postdose. The value of CLr was calculated as Ae,u/AUCt. | Day 1 to Day 8 |
| Number of Adverse Events (AEs) Reported | AEs were captured for all participants from the time the ICF was signed until the end of the study | From the time the Informed Consent Form was signed, throughout the 8 day study up to 30 days after study drug administration. |
| Number of Participants With Changes From Baseline in Vital Signs Parameters. | Vital signs (including blood pressure, heart rate, temperature, and respiratory rate) were assessed at Screening, Day -1, Day 1 at predose (within 45 minutes prior to dosing), and 2, 4, 6, 8, 12, 24, 72, 120, and 168/ET hours postdose. Blood pressure and heart rate were taken with the subject in the supine (performed first), sitting, and standing | Day -1 to Day 8 |
| Number of Participants With Changes From Baseline in Electrocardiogram (ECG) Parameters. | Electrocardiograms were performed at Screening, Day -1, and Day 1 at predose (in triplicate; within 45 minutes prior to dosing), and 2, 4, 6, 8, 12, 24, 72, 120, and 168/ET hours postdose. Standard 12-lead ECGs were performed after the subject was supine and at rest for ≥ 10 minutes prior to the ECG. | Day-1 to Day 8 |
| Number of Participants With Changes From Baseline in Serum Chemistry, Hematology and Urinalysis Parameters. | Hematology, serum chemistry, and urinalysis, including prothrombin time, international normalized ratio, partial thromboplastin time, and activated partial thromboplastin time, were completed at Screening, Day -1, Day 3 (48 hours postdose), and Day 8 (168 hours postdose)/ET. | Day -1 to Day 8 |
| Incidence of Suicidality, Suicidal Behaviour or Suicidal Ideation as Measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) | The Baseline version of the C-SSRS was administered at Screening. The Since Last Visit version of the C-SSRS was administered on Day 1 at predose and on Days 4 and 7. | Day 1, Day 4, Day 7 |
| Minneapolis |
| Minnesota |
| 55404 |
| United States |
| Study Site | San Antonio | Texas | 78212 | United States |
Participants with moderate hepatic impairment (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 mg.
| BG002 | Severe Hepatic Impairment | Participants with severe hepatic impairment (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 mg. |
| BG003 | Normal Hepatic Function | Participants with normal hepatic impairment (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 mg. |
| BG004 | Total | Total of all reporting groups |
| Years |
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| Sex: Female, Male | Count of Participants | Participants |
|
Participants with normal hepatic function received a single oral dose of brexpiprazole 2 mg. Each participant with normal hepatic function was matched to a participant with hepatic impairment by age (within the decile or ± 5 years, whichever was less), sex, and weight (± 15%). Participants with hepatic impairment and within 30% of their ideal body weight (minimum body weight of 50 kg) were enrolled. |
| OG002 | Moderate Hepatic Impairment | Participants with moderate hepatic impairment (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 mg. |
| OG003 | Normal Hepatic Function Matched to Moderate Hepatic Function. | Participants with normal hepatic function received a single oral dose of brexpiprazole 2 mg. Each participant with normal hepatic function was matched to a subject with hepatic impairment by age (within the decile or ± 5 years, whichever was less), sex, and weight (± 15%). Participants with hepatic impairment and within 30% of their ideal body weight (minimum body weight of 50 kg) were enrolled. |
| OG004 | Severe Hepatic Impairment | Participants with severe hepatic impairment (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 mg. |
| OG005 | Normal Hepatic Function Matched to Severe Hepatic Function. | Participants with normal hepatic function received a single oral dose of brexpiprazole 2 mg. Each participant with normal hepatic function was matched to a participant with hepatic impairment by age (within the decile or ± 5 years, whichever was less), sex, and weight (± 15%). Participants with hepatic impairment and within 30% of their ideal body weight (minimum body weight of 50 kg) were enrolled. |
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| Primary | Unbound Brexpiprazole AUC Calculated From Time Zero to Infinity (AUC∞,u) | Blood samples were taken at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. AUC (0 - ∞)= AUC from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | ng*h/mL | Day 1 to Day 8 |
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| Primary | Unbound Maximum Plasma Concentration of Brexpiprazole (Cmax,u) | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. Cmax,u is the highest measured unbound plasma concentration during the dosing interval. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | ng/mL | Day 1 to Day 8 |
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| Secondary | Area Under the Curve of Brexpiprazole Calculated to the Last Observable Concentration at Time t (AUCt) | Blood samples were taken at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. AUCt= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t) The AUCt was estimated using the linear trapezoidal rule. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | ng*h/mL | Day 1 to Day 8 |
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| Secondary | Area Under the Concentration Time Curve of Brexpiprazole From Time Zero to Infinity (AUC∞) | Blood samples were taken at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. AUC (0 - ∞)= AUC from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). The AUC∞ was estimated using the linear trapezoidal rule | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | ng*h/mL | Day 1 to Day 8 |
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| Secondary | Maximum Plasma Concentration of Brexpiprazole (Cmax) | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. Cmax is the highest measured concentration of the drug during the dosing interval. Actual blood sample times were used for PK calculations. Values for Cmax and tmax were determined directly from the observed data. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | ng/mL | Day 1 to Day 8 |
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| Secondary | Time to Cmax of Brexiprazole (Tmax) | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. Tmax is the time taken to reach highest measured concentration of the drug during the dosing interval. Actual blood sample times were used for PK calculations. Values for Cmax and tmax were determined directly from the observed data. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Median | Full Range | h | Day 1 to Day 8 |
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| Secondary | Apparent Clearance of Brexpiprazole From Plasma After Extravascular Administration (CL/F) | The value of CL/F (brexpiprazole only) was determined as Dose/AUC∞. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | mL/h/kg | Day 1 to Day 8 |
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| Secondary | Unbound Fraction of Brexpiprazole in Plasma (fu) | Blood samples were taken at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | % unbound drug in the urine | Day 1 to Day 8 |
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| Secondary | Apparent Unbound Clearance of Brexpiprazole From Plasma After Extravascular Administration (CLu/F) | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. The value of CLu/F (brexpiprazole only) was determined as dose normalized unbound area under the concentration-time curve from time zero to infinity (Dose/AUC∞,u). | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | mL/h/kg | Day 1 to Day 8 |
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| Secondary | Terminal-phase Elimination Half-life of Brexpiprazole (t1/2,z) | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. The t1/2,z was determined as (ln2)/λz. Terminal-phase elimination half-life is the time measured for the plasma concentration to decrease by one half. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | h | Day 1 to Day 8 |
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| Secondary | Renal Clearance (CLr) of Brexipiprazole | Urine samples were taken at pre-dose and during the following increments: 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours postdose. The value of CLr was calculated as Ae,u/AUCt. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | mL/h/kg | Day 1 to Day 8 |
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| Secondary | Cumulative Amount of Brexpiprazole Excreted Into the Urine (Ae,u) | Urine samples were taken at pre-dose and during the following increments: 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours postdose. The value of Ae,u was calculated as the summation of urine concentration × urine volume from each collection interval | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | ng | Day 1 to Day 8 |
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| Secondary | Fraction of Systemically Available Brexpiprazole Excreted Into the Urine (fe,u) | Urine samples were taken at pre-dose and during the following increments: 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours postdose.. The value of fe,u was calculated as 100 × Ae,u/Dose. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | % of drug in urine | Day 1 to Day 8 |
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| Secondary | AUCt for DM-3411 Metabolite | Blood samples were taken at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. AUCt= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t) The AUCt was estimated using the linear trapezoidal rule. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | ng*h/mL | Day 1 to Day 8 |
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| Secondary | AUC∞ for DM-3411 Metabolite | Blood samples were taken at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. The AUC∞ were estimated using the linear trapezoidal rule. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | ng*h/mL | Day 1 to Day 8 |
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| Secondary | Cmax for DM-3411 Metabolite | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. Cmax is the highest measured concentration of the metabolite during the dosing interval. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | ng/mL | Day 1 to Day 8 |
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| Secondary | Tmax for DM-3411 Metabolite | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. Tmax is the time taken to reach highest measured concentration of the metabolite during the dosing interval. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Median | Full Range | h | Day 1 to Day 8 |
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| Secondary | t1/2,z for DM-3411 Metabolite | Blood samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose/ET. The t1/2,z was determined as (ln2)/λz. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | h | Day 1 to Day 8 |
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| Secondary | Ae,u for DM-3411 Metabolite | Urine samples were taken at pre-dose and during the following increments: 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours postdose. The value of Ae,u was calculated as the summation of urine concentration × urine volume from each collection interval. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | ng | Day 1 to Day 8 |
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| Secondary | fe,u for DM-3411 Metabolite | Urine samples were taken at pre-dose and during the following increments: 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours postdose. The value of fe,u was calculated as 100 × Ae,u/Dose. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | % metabolite excreted in urine | Day 1 to Day 8 |
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| Secondary | CLr for DM-3411 Metabolite | Urine samples were taken at pre-dose and during the following increments: 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 hours postdose. The value of CLr was calculated as Ae,u/AUCt. | PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations. | Posted | Mean | Standard Deviation | mL/h/kg | Day 1 to Day 8 |
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| Secondary | Number of Adverse Events (AEs) Reported | AEs were captured for all participants from the time the ICF was signed until the end of the study | Participants who received at least one dose of study drug were included in the safety analysis. | Posted | Number | Events | From the time the Informed Consent Form was signed, throughout the 8 day study up to 30 days after study drug administration. |
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| Secondary | Number of Participants With Changes From Baseline in Vital Signs Parameters. | Vital signs (including blood pressure, heart rate, temperature, and respiratory rate) were assessed at Screening, Day -1, Day 1 at predose (within 45 minutes prior to dosing), and 2, 4, 6, 8, 12, 24, 72, 120, and 168/ET hours postdose. Blood pressure and heart rate were taken with the subject in the supine (performed first), sitting, and standing | The abnormal values of vital signs values in participants are captured as serious AEs/AEs and are reported in the SAE or other AE section of this results report. | Posted | Number | Participants | Day -1 to Day 8 |
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| Secondary | Number of Participants With Changes From Baseline in Electrocardiogram (ECG) Parameters. | Electrocardiograms were performed at Screening, Day -1, and Day 1 at predose (in triplicate; within 45 minutes prior to dosing), and 2, 4, 6, 8, 12, 24, 72, 120, and 168/ET hours postdose. Standard 12-lead ECGs were performed after the subject was supine and at rest for ≥ 10 minutes prior to the ECG. | The abnormal values of ECG values in participants are captured as serious AEs/AEs and are reported in the SAE or other AE section of this results report. | Posted | Number | Participants | Day-1 to Day 8 |
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| Secondary | Number of Participants With Changes From Baseline in Serum Chemistry, Hematology and Urinalysis Parameters. | Hematology, serum chemistry, and urinalysis, including prothrombin time, international normalized ratio, partial thromboplastin time, and activated partial thromboplastin time, were completed at Screening, Day -1, Day 3 (48 hours postdose), and Day 8 (168 hours postdose)/ET. | The abnormal values of laboratory values in participants are captured as serious AEs/AEs and are reported in the SAE or other AE section of this results report. | Posted | Number | Participant | Day -1 to Day 8 |
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| Secondary | Incidence of Suicidality, Suicidal Behaviour or Suicidal Ideation as Measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) | The Baseline version of the C-SSRS was administered at Screening. The Since Last Visit version of the C-SSRS was administered on Day 1 at predose and on Days 4 and 7. | Suicidality, suicidal behaviour or suicidal ideation are captured as serious AEs/AEs and are reported in the SAE or other AE section of this results report. | Posted | Number | Participants | Day 1, Day 4, Day 7 |
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| 0 |
| 8 |
| 3 |
| 8 |
| EG001 | Moderate Hepatic Impairment | Participants with moderate hepatic impairment (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 mg. | 0 | 8 | 3 | 8 |
| EG002 | Severe Hepatic Impairment | Participants with severe hepatic impairment (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 mg. | 0 | 6 | 1 | 6 |
| EG003 | Normal Hepatic Function | Participants with normal hepatic function (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 mg. | 0 | 23 | 6 | 23 |
| Fatigue | General disorders | MedDRA | Non-systematic Assessment |
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| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA | Non-systematic Assessment |
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| Somnolence | Nervous system disorders | MedDRA | Non-systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA | Non-systematic Assessment |
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Not provided
Not provided
Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The primary comparison was each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the primary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance. | Mixed effect analysis of variance | Geometric Mean Ratio | 1.727 | 2-Sided | 90 | 0.977 | 3.052 | Due to the nature of the normal-theory CIs, this approach is equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The primary comparison was each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the primary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance | Mixed effect analysis of variance | Geometic Mean Ratio | 1.041 | 2-Sided | 90 | 0.506 | 2.142 | Due to the nature of the normal-theory CIs, this approach is equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The primary comparison was each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the primary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance | Mixed effect analysis of variance | Geometric Mean Ratio | 0.850 | 2-Sided | 90 | 0.665 | 1.087 | Due to the nature of the normal-theory CIs, this approach is equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The primary comparison was each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the primary PK parameters between each hepatic disease group and the control group, the 90% confidence interval (CI) for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance | Mixed effect analysis of variance | Geometric Mean Ratio | 0.531 | 90 | 0.399 | 0.705 | Due to the nature of the normal-theory CIs, this approach is equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The secondary comparisons were each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the secondary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance. | Mixed effect analysis of variance | Geometric Mean Ratio | 1.199 | 2-Sided | 90 | 0.841 | 1.710 | Due to the nature of the normal-theory CIs, this approach is equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The secondary comparisons were each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the secondary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance. | Mixed effect analysis of variance | Geometric Mean Ratio | 0.790 | 2-Sided | 90 | 0.524 | 1.189 | Due to the nature of the normal-theory CIs, this approach is equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The secondary comparisons were each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the secondary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance. | Mixed effect analysis of variance | Geometric Mean Ratio | 1.604 | 2-Sided | 90 | 0.942 | 2.732 | Due to the nature of the normal-theory CIs, this approach is equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance |
| The secondary comparisons were each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the secondary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance. | Mixed effect analysis of variance | Geometric Mean Ratio | 1.077 | 2-Sided | 90 | 0.540 | 2.146 | Due to the nature of the normal-theory CIs, this approach is equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The secondary comparisons were each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the secondary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance. | Mixed effect analysis of variance | Geometric Mean Ratio | 0.742 | 2-Sided | 90 | 0.599 | 0.918 | Due to the nature of the normal-theory CIs, this approach is equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The secondary comparisons were each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the secondary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance. | Mixed effect analysis of variance | Geometric Mean Ratio | 0.451 | 2-Sided | 90 | 0.352 | 0.577 | Due to the nature of the normal-theory CIs, this approach is equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The secondary comparisons were each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the secondary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance. | Mixed effect analysis of variance | Geometric Mean Ratio | 0.586 | 2-Sided | 90 | 0.399 | 0.861 | Due to the nature of the normal-theory CIs, this approach is equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The secondary comparisons were each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the secondary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance. | Mixed effect analysis of variance | Geometric Mean Ratio | 0.334 | 2-Sided | 90 | 0.214 | 0.521 | Due to the nature of the normal-theory CIs, this approach is equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The secondary comparisons were each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the secondary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance. | Mixed effect analysis of variance | Geometric Mean Ratio | 0.594 | 2-Sided | 90 | 0.378 | 0.934 | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The secondary comparisons were each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the secondary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance. | Mixed effect analysis of variance | Geometric Mean Ratio | 0.561 | 2-Sided | 90 | 0.308 | 1.022 | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The secondary comparisons were each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the secondary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance. | Mixed effect analysis of variance | Geometric Mean Ratio | 0.516 | 2-Sided | 90 | 0.341 | 0.781 | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| The secondary comparisons were each hepatic disease group (mild, moderate or severe) versus the control (normal group). To compare the secondary PK parameters between each hepatic disease group and the control group, the 90% CI for the difference in the means of the log-transformed data was calculated using a mixed effect analysis of variance. | Mixed effect analysis of variance | Geometric Mean Ratio | 0.314 | 2-Sided | 90 | 0.195 | 0.507 | Yes | Non-Inferiority or Equivalence | Bioequivalence was claimed for a PK parameter if the 90% CI for the ratio of the geometric means of a PK variable fell within the interval [0.5, 2.0]. Due to the nature of the normal-theory CIs, this approach was equivalent to carrying out two 1-sided tests of hypothesis at the 5% level of significance. |
| Treatment emergent adverse events |
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| Serious adverse events |
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