A Study Evaluating the of OPC-34712 in Subjects With Normal Hepatic Function and Hepatically Impaired Subjects

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Single-dose, Open-label, Parallel Group, Matched Study Evaluating the Pharmacokinetics of Oral OPC-34712 Tablet in Subjects With Normal Hepatic Function and Hepatically Impaired Subjects

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: OPC-34712


Participation Criteria
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Eligibility Criteria
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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. Exclusion Criteria for Hepatically Impaired Subjects Only: History of serious mental disorder including subjects who are pre-encephalopathic or encephalopathic as assessed by the Child-Pugh score and/or the PI's judgment. Major surgery of the digestive tract. Exclusion Criteria for Subjects with Normal Hepatic Function Only: Clinically significant abnormality in past medical history. History of or current hepatitis, or carriers of HBsAg and/or anti-HC. Use of prescription, over-the-counter, herbal medication or vitamin supplements within 14 days prior to dosing and antibiotics within 30 days prior to dosing. History of serious mental disorders. Major surgery of the digestive tract (excluding appendectomy).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Normal<br> | Drug: OPC-34712<br>* 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.<br>|
| Active Comparator: Mild<br> | Drug: OPC-34712<br>* 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.<br>|
| Active Comparator: Moderate<br> | Drug: OPC-34712<br>* 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.<br>|
| Active Comparator: Severe<br> | Drug: OPC-34712<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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. | 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 |