Schizophrenia
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGOPC-34712
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.
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Males and females of non-childbearing potential ≥ 18 years of age * Body weight within ± 30% of ideal body weight as defined in the 1983 Metropolitan Height and Weight Tables. Minimum body weight no less than 50 kg. * Able to provide written, informed consent. * Male and female subjects who are surgically sterile; female subjects who have been postmenopausal for at least 12 consecutive months; or male subjects who agree to remain abstinent or to practice double-barrier forms of birth control and refrain from sperm donation from Screening through 90 days from the last dose of study medication. Inclusion Criteria for Hepatically Impaired Subjects Only: * Hepatically impaired subjects with creatinine clearance (CLcr) \> 30 mL/min. * Subjects with hepatic impairment should have relatively stable hepatic function for the duration of the study, and otherwise be in generally good health. * A clinical diagnosis of hepatic cirrhosis based on biopsy and/or clinical criteria. * Child-Pugh Class A (mild), B (moderate), or C (severe) * Hepatically impaired subjects may be taking medications, which in the opinion of the clinical investigator and sponsor, are believed to be therapeutic for the subjects. * Hepatically impaired subjects may have a history of or current hepatitis or be carriers of hepatitis B surface antigen (HBsAg) and/or hepatitis C antibodies (anti-HC). Inclusion Criteria for Subjects with Normal Hepatic Function Only * Must be in good health as determined by medical history, physical examination, ECG, serum/urine biochemistry, hematology, and serology tests. * Normal renal function as evidenced by CLcr that is within 20% of normal for the age, sex, and weight of the individual.
Exclusion criteria
* History of drug and/or alcohol abuse within 2 years prior to Screening. * History of acquired immunodeficiency syndrome or human immunodeficiency virus (HIV) antibodies. * History of any significant drug allergy or known or suspected hypersensitivity. * A positive urine alcohol test and/or urine drug screen for substance of abuse at Screening or upon admission to the study center. * Subjects having taken an investigational drug within 30 days preceding study entry. * Any history of significant bleeding or hemorrhagic tendencies. Subjects with a history of bleeding tendencies secondary to hepatic impairment will not be excluded. * A history of difficulty in donating blood. * The donation of blood or plasma within 30 days prior to dosing. * Consumption of alcohol and/or food and beverages containing methylxanthines, grapefruit, grapefruit juice, Seville oranges, or Seville orange juice within 72 hours prior to dosing. * Exposure to any substances known to stimulate hepatic microsomal enzymes within 30 days prior to Screening through the end of the study. * Subjects who have supine, sitting, or standing blood pressure, after resting for ≥ 3 minutes, higher than 140/90 mmHg or lower than 100/50 mmHg. * Subjects who have a supine pulse rate, after resting for ≥ 3 minutes, outside the range of 40 to 90 bpm. * Previous exposure to OPC-34712. * Subjects who are pregnant or breastfeeding. * Subjects with a QTcF interval ≥ 450 msec. * Subjects with PT greater than 2 times control. Subjects with hepatic impairment with prolonged PT will be excluded based on the PI's discretion. * Subjects with hepatic carcinoma or porto-hepatic shunts that have been surgically created or planted. * Partial thromboplastin time \> 70 seconds.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Unbound Brexpiprazole Area Under the Concentration Time Curve (AUC) Calculated to the Last Observable Concentration at Time t (AUCt,u) | Day 1 to Day 8 | 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). |
| Unbound Brexpiprazole AUC Calculated From Time Zero to Infinity (AUC∞,u) | Day 1 to Day 8 | 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 - ∞). |
| Unbound Maximum Plasma Concentration of Brexpiprazole (Cmax,u) | Day 1 to Day 8 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Cmax of Brexiprazole (Tmax) | Day 1 to Day 8 | 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. |
| Apparent Clearance of Brexpiprazole From Plasma After Extravascular Administration (CL/F) | Day 1 to Day 8 | 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. |
| Unbound Fraction of Brexpiprazole in Plasma (fu) | Day 1 to Day 8 | 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. |
| Apparent Unbound Clearance of Brexpiprazole From Plasma After Extravascular Administration (CLu/F) | Day 1 to Day 8 | 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). |
| Terminal-phase Elimination Half-life of Brexpiprazole (t1/2,z) | Day 1 to Day 8 | 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. |
| Renal Clearance (CLr) of Brexipiprazole | Day 1 to Day 8 | 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. |
| Cumulative Amount of Brexpiprazole Excreted Into the Urine (Ae,u) | Day 1 to Day 8 | 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 |
| Fraction of Systemically Available Brexpiprazole Excreted Into the Urine (fe,u) | Day 1 to Day 8 | 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. |
| AUCt for DM-3411 Metabolite | Day 1 to Day 8 | 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. |
| AUC∞ for DM-3411 Metabolite | Day 1 to Day 8 | 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. |
| Area Under the Curve of Brexpiprazole Calculated to the Last Observable Concentration at Time t (AUCt) | Day 1 to Day 8 | 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. |
| Tmax for DM-3411 Metabolite | Day 1 to Day 8 | 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. |
| t1/2,z for DM-3411 Metabolite | Day 1 to Day 8 | 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. |
| Ae,u for DM-3411 Metabolite | Day 1 to Day 8 | 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. |
| fe,u for DM-3411 Metabolite | Day 1 to Day 8 | 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. |
| CLr for DM-3411 Metabolite | Day 1 to Day 8 | 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. |
| Number of Adverse Events (AEs) Reported | From the time the Informed Consent Form was signed, throughout the 8 day study up to 30 days after study drug administration. | AEs were captured for all participants from the time the ICF was signed until the end of the study |
| Number of Participants With Changes From Baseline in Vital Signs Parameters. | Day -1 to Day 8 | 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 |
| Number of Participants With Changes From Baseline in Electrocardiogram (ECG) Parameters. | Day-1 to Day 8 | 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. |
| Number of Participants With Changes From Baseline in Serum Chemistry, Hematology and Urinalysis Parameters. | Day -1 to Day 8 | 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. |
| Incidence of Suicidality, Suicidal Behaviour or Suicidal Ideation as Measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) | Day 1, Day 4, Day 7 | 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. |
| Cmax for DM-3411 Metabolite | Day 1 to Day 8 | 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. |
| Area Under the Concentration Time Curve of Brexpiprazole From Time Zero to Infinity (AUC∞) | Day 1 to Day 8 | 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 |
| Maximum Plasma Concentration of Brexpiprazole (Cmax) | Day 1 to Day 8 | 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. |
Countries
United States
Participant flow
Recruitment details
81 participants were screened; of these 45 participants were enrolled recruited at 3 study sites in the United States (US).
Participants by arm
| Arm | Count |
|---|---|
| Mild Hepatic Impairment Participants with mild hepatic impairment (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 mg. | 8 |
| Moderate Hepatic Impairment Participants with moderate hepatic impairment (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 mg. | 8 |
| Severe Hepatic Impairment Participants with severe hepatic impairment (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 mg. | 6 |
| Normal Hepatic Function Participants with normal hepatic impairment (Child-Pugh classification scheme) received a single oral dose of brexpiprazole 2 mg. | 23 |
| Total | 45 |
Baseline characteristics
| Characteristic | Mild Hepatic Impairment | Moderate Hepatic Impairment | Severe Hepatic Impairment | Normal Hepatic Function | Total |
|---|---|---|---|---|---|
| Age, Continuous | 59.5 Years STANDARD_DEVIATION 7.3 | 57.8 Years STANDARD_DEVIATION 3.8 | 51.2 Years STANDARD_DEVIATION 4.4 | 56.2 Years STANDARD_DEVIATION 5.2 | 56.4 Years STANDARD_DEVIATION 5.7 |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 0 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 6 Participants | 18 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 8 | 3 / 8 | 1 / 6 | 6 / 23 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 6 | 0 / 23 |
Outcome results
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).
Time frame: Day 1 to Day 8
Population: Pharmacokinetics (PK) set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Unbound Brexpiprazole Area Under the Concentration Time Curve (AUC) Calculated to the Last Observable Concentration at Time t (AUCt,u) | 5.95 nanograms.hours/mL (ng*h/mL) | Standard Deviation 2.58 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Unbound Brexpiprazole Area Under the Concentration Time Curve (AUC) Calculated to the Last Observable Concentration at Time t (AUCt,u) | 4.87 nanograms.hours/mL (ng*h/mL) | Standard Deviation 1.78 |
| Moderate Hepatic Impairment | Unbound Brexpiprazole Area Under the Concentration Time Curve (AUC) Calculated to the Last Observable Concentration at Time t (AUCt,u) | 5.41 nanograms.hours/mL (ng*h/mL) | Standard Deviation 1.37 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Unbound Brexpiprazole Area Under the Concentration Time Curve (AUC) Calculated to the Last Observable Concentration at Time t (AUCt,u) | 4.28 nanograms.hours/mL (ng*h/mL) | Standard Deviation 1.95 |
| Severe Hepatic Impairment | Unbound Brexpiprazole Area Under the Concentration Time Curve (AUC) Calculated to the Last Observable Concentration at Time t (AUCt,u) | 3.27 nanograms.hours/mL (ng*h/mL) | Standard Deviation 0.93 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Unbound Brexpiprazole Area Under the Concentration Time Curve (AUC) Calculated to the Last Observable Concentration at Time t (AUCt,u) | 3.63 nanograms.hours/mL (ng*h/mL) | Standard Deviation 1.54 |
Comparison: 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.90% CI: [0.776, 1.751]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.915, 2.066]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.581, 1.488]Mixed effect analysis of variance
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 - ∞).
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Unbound Brexpiprazole AUC Calculated From Time Zero to Infinity (AUC∞,u) | 8.59 ng*h/mL | Standard Deviation 5.29 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Unbound Brexpiprazole AUC Calculated From Time Zero to Infinity (AUC∞,u) | 5.85 ng*h/mL | Standard Deviation 3.11 |
| Moderate Hepatic Impairment | Unbound Brexpiprazole AUC Calculated From Time Zero to Infinity (AUC∞,u) | 8.50 ng*h/mL | Standard Deviation 2.17 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Unbound Brexpiprazole AUC Calculated From Time Zero to Infinity (AUC∞,u) | 5.62 ng*h/mL | Standard Deviation 3.13 |
| Severe Hepatic Impairment | Unbound Brexpiprazole AUC Calculated From Time Zero to Infinity (AUC∞,u) | 3.49 ng*h/mL | Standard Deviation 0.848 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Unbound Brexpiprazole AUC Calculated From Time Zero to Infinity (AUC∞,u) | 3.36 ng*h/mL | Standard Deviation 0.871 |
Comparison: 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.90% CI: [0.702, 2.244]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.977, 3.052]Mixed effect analysis of variance
Comparison: 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 variance90% CI: [0.506, 2.142]Mixed effect analysis of variance
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Unbound Maximum Plasma Concentration of Brexpiprazole (Cmax,u) | 0.104 ng/mL | Standard Deviation 0.0259 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Unbound Maximum Plasma Concentration of Brexpiprazole (Cmax,u) | 0.114 ng/mL | Standard Deviation 0.027 |
| Moderate Hepatic Impairment | Unbound Maximum Plasma Concentration of Brexpiprazole (Cmax,u) | 0.0648 ng/mL | Standard Deviation 0.0143 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Unbound Maximum Plasma Concentration of Brexpiprazole (Cmax,u) | 0.0779 ng/mL | Standard Deviation 0.0224 |
| Severe Hepatic Impairment | Unbound Maximum Plasma Concentration of Brexpiprazole (Cmax,u) | 0.0392 ng/mL | Standard Deviation 0.0105 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Unbound Maximum Plasma Concentration of Brexpiprazole (Cmax,u) | 0.0760 ng/mL | Standard Deviation 0.0258 |
Comparison: 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 variance90% CI: [0.707, 1.156]Mixed effect analysis of variance
Comparison: 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 variance90% CI: [0.665, 1.087]Mixed effect analysis of variance
Comparison: 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 variance90% CI: [0.399, 0.705]Mixed effect analysis of variance
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Ae,u for DM-3411 Metabolite | 67086 ng | Standard Deviation 25276 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Ae,u for DM-3411 Metabolite | 81148 ng | Standard Deviation 23188 |
| Moderate Hepatic Impairment | Ae,u for DM-3411 Metabolite | 68413 ng | Standard Deviation 16993 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Ae,u for DM-3411 Metabolite | 71353 ng | Standard Deviation 41630 |
| Severe Hepatic Impairment | Ae,u for DM-3411 Metabolite | 48190 ng | Standard Deviation 14756 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Ae,u for DM-3411 Metabolite | 83604 ng | Standard Deviation 34907 |
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Apparent Clearance of Brexpiprazole From Plasma After Extravascular Administration (CL/F) | 24.5 mL/h/kg | Standard Deviation 28.2 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Apparent Clearance of Brexpiprazole From Plasma After Extravascular Administration (CL/F) | 25.4 mL/h/kg | Standard Deviation 12.3 |
| Moderate Hepatic Impairment | Apparent Clearance of Brexpiprazole From Plasma After Extravascular Administration (CL/F) | 13.8 mL/h/kg | Standard Deviation 2.72 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Apparent Clearance of Brexpiprazole From Plasma After Extravascular Administration (CL/F) | 26.0 mL/h/kg | Standard Deviation 19.2 |
| Severe Hepatic Impairment | Apparent Clearance of Brexpiprazole From Plasma After Extravascular Administration (CL/F) | 28.2 mL/h/kg | Standard Deviation 6.7 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Apparent Clearance of Brexpiprazole From Plasma After Extravascular Administration (CL/F) | 34.2 mL/h/kg | Standard Deviation 16.3 |
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).
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Apparent Unbound Clearance of Brexpiprazole From Plasma After Extravascular Administration (CLu/F) | 5674 mL/h/kg | Standard Deviation 7165 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Apparent Unbound Clearance of Brexpiprazole From Plasma After Extravascular Administration (CLu/F) | 5730 mL/h/kg | Standard Deviation 2944 |
| Moderate Hepatic Impairment | Apparent Unbound Clearance of Brexpiprazole From Plasma After Extravascular Administration (CLu/F) | 3115 mL/h/kg | Standard Deviation 494 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Apparent Unbound Clearance of Brexpiprazole From Plasma After Extravascular Administration (CLu/F) | 6768 mL/h/kg | Standard Deviation 5833 |
| Severe Hepatic Impairment | Apparent Unbound Clearance of Brexpiprazole From Plasma After Extravascular Administration (CLu/F) | 6598 mL/h/kg | Standard Deviation 1182 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Apparent Unbound Clearance of Brexpiprazole From Plasma After Extravascular Administration (CLu/F) | 7697 mL/h/kg | Standard Deviation 2653 |
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
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Area Under the Concentration Time Curve of Brexpiprazole From Time Zero to Infinity (AUC∞) | 1827 ng*h/mL | Standard Deviation 1103 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Area Under the Concentration Time Curve of Brexpiprazole From Time Zero to Infinity (AUC∞) | 1393 ng*h/mL | Standard Deviation 881 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve of Brexpiprazole From Time Zero to Infinity (AUC∞) | 1960 ng*h/mL | Standard Deviation 579 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Area Under the Concentration Time Curve of Brexpiprazole From Time Zero to Infinity (AUC∞) | 1345 ng*h/mL | Standard Deviation 697 |
| Severe Hepatic Impairment | Area Under the Concentration Time Curve of Brexpiprazole From Time Zero to Infinity (AUC∞) | 831 ng*h/mL | Standard Deviation 234 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Area Under the Concentration Time Curve of Brexpiprazole From Time Zero to Infinity (AUC∞) | 788 ng*h/mL | Standard Deviation 230 |
Comparison: 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.90% CI: [0.719, 2.143]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.942, 2.732]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.54, 2.146]Mixed effect analysis of variance
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Area Under the Curve of Brexpiprazole Calculated to the Last Observable Concentration at Time t (AUCt) | 1271 ng*h/mL | Standard Deviation 569 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Area Under the Curve of Brexpiprazole Calculated to the Last Observable Concentration at Time t (AUCt) | 1145 ng*h/mL | Standard Deviation 539 |
| Moderate Hepatic Impairment | Area Under the Curve of Brexpiprazole Calculated to the Last Observable Concentration at Time t (AUCt) | 1213 ng*h/mL | Standard Deviation 405 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Area Under the Curve of Brexpiprazole Calculated to the Last Observable Concentration at Time t (AUCt) | 1048 ng*h/mL | Standard Deviation 422 |
| Severe Hepatic Impairment | Area Under the Curve of Brexpiprazole Calculated to the Last Observable Concentration at Time t (AUCt) | 622 ng*h/mL | Standard Deviation 163 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Area Under the Curve of Brexpiprazole Calculated to the Last Observable Concentration at Time t (AUCt) | 817 ng*h/mL | Standard Deviation 306 |
Comparison: 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.90% CI: [0.774, 1.573]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.841, 1.71]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.524, 1.189]Mixed effect analysis of variance
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | AUC∞ for DM-3411 Metabolite | 489 ng*h/mL | Standard Deviation 210 |
| Normal Hepatic Function Matched to Mild Hepatic Function | AUC∞ for DM-3411 Metabolite | 692 ng*h/mL | Standard Deviation 259 |
| Moderate Hepatic Impairment | AUC∞ for DM-3411 Metabolite | 382 ng*h/mL | Standard Deviation 262 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | AUC∞ for DM-3411 Metabolite | 530 ng*h/mL | Standard Deviation 211 |
| Severe Hepatic Impairment | AUC∞ for DM-3411 Metabolite | 187 ng*h/mL | Standard Deviation 67.2 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | AUC∞ for DM-3411 Metabolite | 329 ng*h/mL | Standard Deviation 167 |
Comparison: 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.90% CI: [0.445, 1.153]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.378, 0.934]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.308, 1.022]Mixed effect analysis of variance
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | AUCt for DM-3411 Metabolite | 380 ng*h/mL | Standard Deviation 195 |
| Normal Hepatic Function Matched to Mild Hepatic Function | AUCt for DM-3411 Metabolite | 683 ng*h/mL | Standard Deviation 246 |
| Moderate Hepatic Impairment | AUCt for DM-3411 Metabolite | 284 ng*h/mL | Standard Deviation 164 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | AUCt for DM-3411 Metabolite | 486 ng*h/mL | Standard Deviation 263 |
| Severe Hepatic Impairment | AUCt for DM-3411 Metabolite | 151 ng*h/mL | Standard Deviation 51.4 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | AUCt for DM-3411 Metabolite | 479 ng*h/mL | Standard Deviation 226 |
Comparison: 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.90% CI: [0.346, 0.748]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.399, 0.861]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.214, 0.521]Mixed effect analysis of variance
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | CLr for DM-3411 Metabolite | 2.67 mL/h/kg | Standard Deviation 1.31 |
| Normal Hepatic Function Matched to Mild Hepatic Function | CLr for DM-3411 Metabolite | 1.83 mL/h/kg | Standard Deviation 0.828 |
| Moderate Hepatic Impairment | CLr for DM-3411 Metabolite | 3.96 mL/h/kg | Standard Deviation 2.32 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | CLr for DM-3411 Metabolite | 1.90 mL/h/kg | Standard Deviation 0.568 |
| Severe Hepatic Impairment | CLr for DM-3411 Metabolite | 4.08 mL/h/kg | Standard Deviation 1.68 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | CLr for DM-3411 Metabolite | 2.33 mL/h/kg | Standard Deviation 1.01 |
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Cmax for DM-3411 Metabolite | 6.49 ng/mL | Standard Deviation 5.13 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Cmax for DM-3411 Metabolite | 10.5 ng/mL | Standard Deviation 4.26 |
| Moderate Hepatic Impairment | Cmax for DM-3411 Metabolite | 3.19 ng/mL | Standard Deviation 1.56 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Cmax for DM-3411 Metabolite | 7.25 ng/mL | Standard Deviation 4.83 |
| Severe Hepatic Impairment | Cmax for DM-3411 Metabolite | 2.15 ng/mL | Standard Deviation 0.88 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Cmax for DM-3411 Metabolite | 7.13 ng/mL | Standard Deviation 3.73 |
Comparison: 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.90% CI: [0.368, 0.845]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.341, 0.781]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.195, 0.507]Mixed effect analysis of variance
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
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Cumulative Amount of Brexpiprazole Excreted Into the Urine (Ae,u) | 4511 ng | Standard Deviation 3808 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Cumulative Amount of Brexpiprazole Excreted Into the Urine (Ae,u) | 1854 ng | Standard Deviation 1500 |
| Moderate Hepatic Impairment | Cumulative Amount of Brexpiprazole Excreted Into the Urine (Ae,u) | 3522 ng | Standard Deviation 2740 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Cumulative Amount of Brexpiprazole Excreted Into the Urine (Ae,u) | 3837 ng | Standard Deviation 3358 |
| Severe Hepatic Impairment | Cumulative Amount of Brexpiprazole Excreted Into the Urine (Ae,u) | 2090 ng | Standard Deviation 4699 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Cumulative Amount of Brexpiprazole Excreted Into the Urine (Ae,u) | 1326 ng | Standard Deviation 1427 |
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | fe,u for DM-3411 Metabolite | 3.23 % metabolite excreted in urine | Standard Deviation 1.22 |
| Normal Hepatic Function Matched to Mild Hepatic Function | fe,u for DM-3411 Metabolite | 3.91 % metabolite excreted in urine | Standard Deviation 1.12 |
| Moderate Hepatic Impairment | fe,u for DM-3411 Metabolite | 3.30 % metabolite excreted in urine | Standard Deviation 0.819 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | fe,u for DM-3411 Metabolite | 3.44 % metabolite excreted in urine | Standard Deviation 2.01 |
| Severe Hepatic Impairment | fe,u for DM-3411 Metabolite | 2.32 % metabolite excreted in urine | Standard Deviation 0.712 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | fe,u for DM-3411 Metabolite | 4.03 % metabolite excreted in urine | Standard Deviation 1.68 |
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Fraction of Systemically Available Brexpiprazole Excreted Into the Urine (fe,u) | 0.226 % of drug in urine | Standard Deviation 0.19 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Fraction of Systemically Available Brexpiprazole Excreted Into the Urine (fe,u) | 0.0927 % of drug in urine | Standard Deviation 0.075 |
| Moderate Hepatic Impairment | Fraction of Systemically Available Brexpiprazole Excreted Into the Urine (fe,u) | 0.176 % of drug in urine | Standard Deviation 0.137 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Fraction of Systemically Available Brexpiprazole Excreted Into the Urine (fe,u) | 0.192 % of drug in urine | Standard Deviation 0.168 |
| Severe Hepatic Impairment | Fraction of Systemically Available Brexpiprazole Excreted Into the Urine (fe,u) | 0.104 % of drug in urine | Standard Deviation 0.235 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Fraction of Systemically Available Brexpiprazole Excreted Into the Urine (fe,u) | 0.0663 % of drug in urine | Standard Deviation 0.0713 |
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.
Time frame: Day 1, Day 4, Day 7
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mild Hepatic Impairment | Incidence of Suicidality, Suicidal Behaviour or Suicidal Ideation as Measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) | 0 Participants |
| Normal Hepatic Function Matched to Mild Hepatic Function | Incidence of Suicidality, Suicidal Behaviour or Suicidal Ideation as Measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) | 0 Participants |
| Moderate Hepatic Impairment | Incidence of Suicidality, Suicidal Behaviour or Suicidal Ideation as Measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) | 0 Participants |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Incidence of Suicidality, Suicidal Behaviour or Suicidal Ideation as Measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) | 0 Participants |
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Maximum Plasma Concentration of Brexpiprazole (Cmax) | 22.9 ng/mL | Standard Deviation 7.6 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Maximum Plasma Concentration of Brexpiprazole (Cmax) | 26.7 ng/mL | Standard Deviation 9.09 |
| Moderate Hepatic Impairment | Maximum Plasma Concentration of Brexpiprazole (Cmax) | 14.6 ng/mL | Standard Deviation 4.63 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Maximum Plasma Concentration of Brexpiprazole (Cmax) | 19.3 ng/mL | Standard Deviation 4.98 |
| Severe Hepatic Impairment | Maximum Plasma Concentration of Brexpiprazole (Cmax) | 7.65 ng/mL | Standard Deviation 2.69 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Maximum Plasma Concentration of Brexpiprazole (Cmax) | 17.7 ng/mL | Standard Deviation 7.38 |
Comparison: 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.90% CI: [0.691, 1.059]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.599, 0.918]Mixed effect analysis of variance
Comparison: 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.90% CI: [0.352, 0.577]Mixed effect analysis of variance
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
Time frame: From the time the Informed Consent Form was signed, throughout the 8 day study up to 30 days after study drug administration.
Population: Participants who received at least one dose of study drug were included in the safety analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mild Hepatic Impairment | Number of Adverse Events (AEs) Reported | Serious adverse events | 0 Events |
| Mild Hepatic Impairment | Number of Adverse Events (AEs) Reported | Treatment emergent adverse events | 3 Events |
| Mild Hepatic Impairment | Number of Adverse Events (AEs) Reported | Adverse events | 3 Events |
| Normal Hepatic Function Matched to Mild Hepatic Function | Number of Adverse Events (AEs) Reported | Serious adverse events | 0 Events |
| Normal Hepatic Function Matched to Mild Hepatic Function | Number of Adverse Events (AEs) Reported | Adverse events | 5 Events |
| Normal Hepatic Function Matched to Mild Hepatic Function | Number of Adverse Events (AEs) Reported | Treatment emergent adverse events | 5 Events |
| Moderate Hepatic Impairment | Number of Adverse Events (AEs) Reported | Treatment emergent adverse events | 1 Events |
| Moderate Hepatic Impairment | Number of Adverse Events (AEs) Reported | Adverse events | 1 Events |
| Moderate Hepatic Impairment | Number of Adverse Events (AEs) Reported | Serious adverse events | 0 Events |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Number of Adverse Events (AEs) Reported | Serious adverse events | 0 Events |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Number of Adverse Events (AEs) Reported | Treatment emergent adverse events | 6 Events |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Number of Adverse Events (AEs) Reported | Adverse events | 8 Events |
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.
Time frame: Day-1 to Day 8
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mild Hepatic Impairment | Number of Participants With Changes From Baseline in Electrocardiogram (ECG) Parameters. | 0 Participants |
| Normal Hepatic Function Matched to Mild Hepatic Function | Number of Participants With Changes From Baseline in Electrocardiogram (ECG) Parameters. | 0 Participants |
| Moderate Hepatic Impairment | Number of Participants With Changes From Baseline in Electrocardiogram (ECG) Parameters. | 0 Participants |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Number of Participants With Changes From Baseline in Electrocardiogram (ECG) Parameters. | 0 Participants |
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.
Time frame: Day -1 to Day 8
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mild Hepatic Impairment | Number of Participants With Changes From Baseline in Serum Chemistry, Hematology and Urinalysis Parameters. | 0 Participant |
| Normal Hepatic Function Matched to Mild Hepatic Function | Number of Participants With Changes From Baseline in Serum Chemistry, Hematology and Urinalysis Parameters. | 0 Participant |
| Moderate Hepatic Impairment | Number of Participants With Changes From Baseline in Serum Chemistry, Hematology and Urinalysis Parameters. | 0 Participant |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Number of Participants With Changes From Baseline in Serum Chemistry, Hematology and Urinalysis Parameters. | 0 Participant |
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
Time frame: Day -1 to Day 8
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mild Hepatic Impairment | Number of Participants With Changes From Baseline in Vital Signs Parameters. | 0 Participants |
| Normal Hepatic Function Matched to Mild Hepatic Function | Number of Participants With Changes From Baseline in Vital Signs Parameters. | 0 Participants |
| Moderate Hepatic Impairment | Number of Participants With Changes From Baseline in Vital Signs Parameters. | 0 Participants |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Number of Participants With Changes From Baseline in Vital Signs Parameters. | 0 Participants |
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Renal Clearance (CLr) of Brexipiprazole | 0.0468 mL/h/kg | Standard Deviation 0.0353 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Renal Clearance (CLr) of Brexipiprazole | 0.0263 mL/h/kg | Standard Deviation 0.0244 |
| Moderate Hepatic Impairment | Renal Clearance (CLr) of Brexipiprazole | 0.0360 mL/h/kg | Standard Deviation 0.0286 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Renal Clearance (CLr) of Brexipiprazole | 0.0422 mL/h/kg | Standard Deviation 0.0383 |
| Severe Hepatic Impairment | Renal Clearance (CLr) of Brexipiprazole | 0.0402 mL/h/kg | Standard Deviation 0.0872 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Renal Clearance (CLr) of Brexipiprazole | 0.0193 mL/h/kg | Standard Deviation 0.0203 |
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | t1/2,z for DM-3411 Metabolite | 78.8 h | Standard Deviation 37.6 |
| Normal Hepatic Function Matched to Mild Hepatic Function | t1/2,z for DM-3411 Metabolite | 59.7 h | Standard Deviation 15.7 |
| Moderate Hepatic Impairment | t1/2,z for DM-3411 Metabolite | 87.2 h | Standard Deviation 45.7 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | t1/2,z for DM-3411 Metabolite | 62.0 h | Standard Deviation 26.4 |
| Severe Hepatic Impairment | t1/2,z for DM-3411 Metabolite | 84.6 h | Standard Deviation 12 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | t1/2,z for DM-3411 Metabolite | 56.1 h | Standard Deviation 8.25 |
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Terminal-phase Elimination Half-life of Brexpiprazole (t1/2,z) | 103 h | Standard Deviation 51.1 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Terminal-phase Elimination Half-life of Brexpiprazole (t1/2,z) | 64.7 h | Standard Deviation 24.6 |
| Moderate Hepatic Impairment | Terminal-phase Elimination Half-life of Brexpiprazole (t1/2,z) | 116 h | Standard Deviation 25.8 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Terminal-phase Elimination Half-life of Brexpiprazole (t1/2,z) | 64.2 h | Standard Deviation 26.2 |
| Severe Hepatic Impairment | Terminal-phase Elimination Half-life of Brexpiprazole (t1/2,z) | 81.1 h | Standard Deviation 17.1 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Terminal-phase Elimination Half-life of Brexpiprazole (t1/2,z) | 51.4 h | Standard Deviation 8.21 |
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mild Hepatic Impairment | Time to Cmax of Brexiprazole (Tmax) | 3.50 h |
| Normal Hepatic Function Matched to Mild Hepatic Function | Time to Cmax of Brexiprazole (Tmax) | 3.50 h |
| Moderate Hepatic Impairment | Time to Cmax of Brexiprazole (Tmax) | 4.50 h |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Time to Cmax of Brexiprazole (Tmax) | 4.50 h |
| Severe Hepatic Impairment | Time to Cmax of Brexiprazole (Tmax) | 5.00 h |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Time to Cmax of Brexiprazole (Tmax) | 5.00 h |
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mild Hepatic Impairment | Tmax for DM-3411 Metabolite | 5.00 h |
| Normal Hepatic Function Matched to Mild Hepatic Function | Tmax for DM-3411 Metabolite | 6.00 h |
| Moderate Hepatic Impairment | Tmax for DM-3411 Metabolite | 5.00 h |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Tmax for DM-3411 Metabolite | 7.00 h |
| Severe Hepatic Impairment | Tmax for DM-3411 Metabolite | 4.5 h |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Tmax for DM-3411 Metabolite | 6.00 h |
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.
Time frame: Day 1 to Day 8
Population: PK set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Impairment | Unbound Fraction of Brexpiprazole in Plasma (fu) | 0.472 % unbound drug in the urine | Standard Deviation 0.084 |
| Normal Hepatic Function Matched to Mild Hepatic Function | Unbound Fraction of Brexpiprazole in Plasma (fu) | 0.451 % unbound drug in the urine | Standard Deviation 0.112 |
| Moderate Hepatic Impairment | Unbound Fraction of Brexpiprazole in Plasma (fu) | 0.462 % unbound drug in the urine | Standard Deviation 0.0786 |
| Normal Hepatic Function Matched to Moderate Hepatic Function. | Unbound Fraction of Brexpiprazole in Plasma (fu) | 0.400 % unbound drug in the urine | Standard Deviation 0.0442 |
| Severe Hepatic Impairment | Unbound Fraction of Brexpiprazole in Plasma (fu) | 0.544 % unbound drug in the urine | Standard Deviation 0.186 |
| Normal Hepatic Function Matched to Severe Hepatic Function. | Unbound Fraction of Brexpiprazole in Plasma (fu) | 0.450 % unbound drug in the urine | Standard Deviation 0.0795 |