Single-dose Iloperidone Pharmacokinetics in Patients With Mild or Moderate Liver Disease, Compared to Healthy Volunteers

Open-label, Single-dose, Parallel-group Study to Compare the PKs of Iloperidone in Subjects With Mild or Moderate Hepatic Impairment With That in Matched Healthy Control Subjects

This study aims to determine the pharmacokinetic profile and the tolerability of iloperidone in subjects with mild or moderate hepatic impairment comparatively to healthy matched subjects

Study Overview

• Status: Completed
• Conditions: Hepatic Impairment
• Intervention / Treatment: Drug: Iloperidone

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Anaheim, California, United States, 92801
      • Novartis Investigative Site
  • Florida
    • Miami, Florida, United States, 33169
      • Novartis Investigative Site
    • Orlando, Florida, United States, 32809
      • Novartis Investigative Site
    • South Miami, Florida, United States, 33143
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Inclusion criteria (all subjects):
• Caucasian subjects
• Inclusion criteria (hepatic impaired subjects):
• subjects with physical signs consistent with a clinical diagnosis of stable liver disease, which has been confirmed by imaging techniques, ultrasound, Magnetic Resonance Imaging or Computed Tomogram within 3 months of screening, and a creatinine clearance > 50 mL/min (based on Cockroft and Gault formula).
• Inclusion criteria (healthy volunteers):
• good general health
• matched by age, gender, smoking status, Body Mass Index, and CYP2D6 phenotype to hepatic impaired subjects.

Exclusion Criteria:

• Exclusion criteria (all subjects):
• Subjects who report smoking a pipe, cigars or more than 20 cigarettes per day .
• History of drug abuse as defined in Diagnostic and Statistical Manual of Mental Disorders, Diagnostic Criteria for Drug and Alcohol Abuse, within the 12 months prior to screening
• History of first-dose response/syncope to alpha1-blocking agents
• Exclusion criteria (Hepatic impaired subjects):
• Patients with symptoms or 6 months past history of encephalopathy.
• Patients with clinical evidence of moderate-severe ascites.
• Patients having a previous surgical porto-systemic shunt.
• Exclusion criteria (Healthy volunteers):
• History of alcohol abuse prior to dosing, or evidence of such abuse during screening.
• Pulse Rate > 200 msec

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Iloperidone; Eligible subjects receive a single oral dose of 2 mg iloperidone as a tablet	Drug: Iloperidone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure: Area Under Curve (AUClast, AUCinf) and maximum concentration (Cmax)	Pharmacokinetics of iloperidone in subjects with mild or moderate hepatic impairment, compared to healthy volunteers.	predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 and 120 hours post-dose
Maximum plasma concentration following drug administration (Cmax) of iloperidone	Blood and urine samples will be collected and plasma and urine concentration will be measured.	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 hours post-dose, and from pre-dose to 48 hours post-dose
Protein binding of iloperidone	Blood samples will be collected and protein binding will be measured .	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 hours post-dose, and from pre-dose to 48 hours post-dose
Area under the plasma concentration-time Curve from time zero to infinity (AUCinf) of iloperidone	Blood and urine samples will be collected and plasma and urine concentration will be measured.	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 hours post-dose, and from pre-dose to 48 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the plasma Curve (AUC) of iloperidone metabolite P88	Blood and urine samples will be collected and plasma and urine concentrations of metabolite 88 will be measured	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 hours post-dose and from pre-dose to 48 hours post-dose
Area under the plasma concentration-time Curve from time zero to infinity (AUCinf) of iloperidone metabolite P88 records, listed by subject. Summary statistics provided by impairment group and visit/time.	Blood and urine samples will be collected and plasma and urine concentrations of metabolite 88 will be measured	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 hours post-dose and from pre-dose to 48 hours post-dose
Maximum plasma concentration following drug administration (Cmax) of iloperidone metabolites P88	Blood and urine samples will be collected and plasma and urine concentrations of metabolite 88 will be measured	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 hours post-dose and from pre-dose to 48 hours post-dose
Protein binding of iloperidone metabolites P88 (CLr)	Blood samples will be collected and protein binding of metabolite 88 will be measured	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 hours post-dose and from pre-dose to 48 hours post-dose
Area Under the plasma Curve (AUC) of iloperidone metabolite P95	Blood and urine samples will be collected and plasma and urine concentrations of metabolite 95 will be measured	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 hours post-dose and from pre-dose to 48 hours post-dose
Area under the plasma concentration-time Curve from time zero to infinity (AUCinf) of iloperidone metabolite P95	Blood and urine samples will be collected and plasma and urine concentrations of metabolite 95 will be measured	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 hours post-dose and from pre-dose to 48 hours post-dose
Maximum plasma concentration following drug administration (Cmax) of iloperidone metabolites P95	Blood and urine samples will be collected and plasma and urine concentrations of metabolite 95 will be measured	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 hours post-dose and from pre-dose to 48 hours post-dose
Protein binding of iloperidone metabolites P95	Blood samples will be collected and protein binding of metabolite 95 will be measured	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120 hours post-dose and from pre-dose to 48 hours post-dose
Number of participants with adverse events	Adverse events will be determined by evaluating clinical, laboratory evaluations, impact on vital signs and impacts on Electrocardiograms (ECGs)	Day 6

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: September 23, 2011
• First Submitted That Met QC Criteria: February 6, 2012
• First Posted (Estimate): February 8, 2012

Study Record Updates

• Last Update Posted (Estimate): March 14, 2013
• Last Update Submitted That Met QC Criteria: March 13, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Hepatic impairment; Iloperidone; ILO522D
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Physiological Effects of Drugs; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Iloperidone
• Other Study ID Numbers: CILO522D2401