Clinical trial NCT01299454: A Study Evaluating the of OPC-34712 in Subjects With Normal Hepatic Function and Hepatically Impaired Subjects
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Schizophrenia
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
First posted: 2011-02-18
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Unbound Brexpiprazole Area Under the Concentration Time Curve (AUC) Calculated to the Last Observable Concentration at Time t (AUCt,u)
timeFrame: Day 1 to Day 8
measure: Unbound Brexpiprazole AUC Calculated From Time Zero to Infinity (AUC∞,u)
timeFrame: Day 1 to Day 8
measure: Unbound Maximum Plasma Concentration of Brexpiprazole (Cmax,u)
timeFrame: Day 1 to Day 8
Secondary outcomes:
measure: Area Under the Curve of Brexpiprazole Calculated to the Last Observable Concentration at Time t (AUCt)
timeFrame: Day 1 to Day 8
measure: Area Under the Concentration Time Curve of Brexpiprazole From Time Zero to Infinity (AUC∞)
timeFrame: Day 1 to Day 8
measure: Maximum Plasma Concentration of Brexpiprazole (Cmax)
timeFrame: Day 1 to Day 8
measure: Time to Cmax of Brexiprazole (Tmax)
timeFrame: Day 1 to Day 8
measure: Apparent Clearance of Brexpiprazole From Plasma After Extravascular Administration (CL/F)
timeFrame: Day 1 to Day 8
measure: Unbound Fraction of Brexpiprazole in Plasma (fu)
timeFrame: Day 1 to Day 8
measure: Apparent Unbound Clearance of Brexpiprazole From Plasma After Extravascular Administration (CLu/F)
timeFrame: Day 1 to Day 8
measure: Terminal-phase Elimination Half-life of Brexpiprazole (t1/2,z)
timeFrame: Day 1 to Day 8
measure: Renal Clearance (CLr) of Brexipiprazole
timeFrame: Day 1 to Day 8
measure: Cumulative Amount of Brexpiprazole Excreted Into the Urine (Ae,u)
timeFrame: Day 1 to Day 8
measure: Fraction of Systemically Available Brexpiprazole Excreted Into the Urine (fe,u)
timeFrame: Day 1 to Day 8
measure: AUCt for DM-3411 Metabolite
timeFrame: Day 1 to Day 8
measure: AUC∞ for DM-3411 Metabolite
timeFrame: Day 1 to Day 8
measure: Cmax for DM-3411 Metabolite
timeFrame: Day 1 to Day 8
measure: Tmax for DM-3411 Metabolite
timeFrame: Day 1 to Day 8
measure: t1/2,z for DM-3411 Metabolite
timeFrame: Day 1 to Day 8
measure: Ae,u for DM-3411 Metabolite
timeFrame: Day 1 to Day 8
measure: fe,u for DM-3411 Metabolite
timeFrame: Day 1 to Day 8
measure: CLr for DM-3411 Metabolite
timeFrame: Day 1 to Day 8
measure: Number of Adverse Events (AEs) Reported
timeFrame: From the time the Informed Consent Form was signed, throughout the 8 day study up to 30 days after study drug administration.
measure: Number of Participants With Changes From Baseline in Vital Signs Parameters.
timeFrame: Day -1 to Day 8
measure: Number of Participants With Changes From Baseline in Electrocardiogram (ECG) Parameters.
timeFrame: Day-1 to Day 8
measure: Number of Participants With Changes From Baseline in Serum Chemistry, Hematology and Urinalysis Parameters.
timeFrame: Day -1 to Day 8
measure: Incidence of Suicidality, Suicidal Behaviour or Suicidal Ideation as Measured by the Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: Day 1, Day 4, Day 7
Other outcomes:
Locations:
city: Miami
country: United States
facility: Study Site
state: Florida
city: Minneapolis
country: United States
facility: Study Site
state: Minnesota
city: San Antonio
country: United States
facility: Study Site
state: Texas
Study officials:
References: