Pharmacokinetics of LCQ908 in Patients With Hepatic Impairment

An Open-label, Single Dose, Parallel-group Study to Evaluate the Pharmacokinetics of LCQ908 in Patients With Mild, Moderate and Severe Hepatic Impairment Compared to Age, Gender and Weight-matched Healthy Volunteers.

This study will compare the pharmacokinetics of LCQ908 in subjects with varying degrees of hepatic impairment to healthy subjects.

Study Overview

• Status: Completed
• Conditions: Hepatic Impairment
• Intervention / Treatment: Drug: LCQ908

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Novartis Investigative Site
    • Orlando, Florida, United States, 32809
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion criteria:

Individuals with hepatic impairment only

• Hepatic impairment evidenced by a Child-Pugh score

• Mild hepatic impairment defined Child-Pugh Class A (5-6 points)
• Moderate hepatic impairment defined Child-Pugh Class B (7-9 points)
• Severe hepatic impairment defined Child-Pugh Class C (10-15 points).

Healthy subjects only

• Good health determined.

Exclusion criteria:

All Individuals

• A past medical history of clinically significant ECG abnormalities or a family history of a prolonged QT-interval syndrome.
• Female subjects must be of non child bearing potential or use an effective method of contraception.

Individuals with hepatic impairment

• History of drug or alcohol abuse within 3 months prior to dosing.
• History or presence of significant uncontrolled disease of any major organ class.
• Any surgical or medical condition other than hepatic impairment which might alter the drug metabolism.

Healthy subjects

• History or presence of significant uncontrolled disease of any major organ class.
• Any surgical or medical condition other than hepatic impairment which might alter the drug metabolism.
• History or presence of hepatitis B or C and/or positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result at screening.

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LCQ908 (mild hepatic impairment plus healthy volunteers); Healthy subjects will be matched pair-wise by, sex, race, age (±10 years) and weight (±20%) to subjects with mild hepatic impairment and will receive a single dose of LCQ908.	Drug: LCQ908; Participants will receive a single oral dose of LCQ908
Experimental: LCQ908 (moderate hepatic impairment plus healthy volunteers); Healthy subjects will be matched pair-wise by, sex, race, age (±10 years) and weight (±20%) to subjects with moderate hepatic impairment and will receive a single dose of LCQ908.	Drug: LCQ908; Participants will receive a single oral dose of LCQ908
Experimental: LCQ908 (severe hepatic impairment plus healthy volunteers); Healthy subjects will be matched pair-wise by, sex, race, age (±10 years) and weight (±20%) to subjects with severe hepatic impairment and will receive a single dose of LCQ908.	Drug: LCQ908; Participants will receive a single oral dose of LCQ908

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (AUClast) of LCQ908 for part I of the study	This outcome applies to Part I of study involving mild and moderate hepatic impairment as well as healthy volunteers. Blood will be collected on Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing followed by additional blood draws on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing.	Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing and on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing
Area under the plasma concentration-time profile from time zero extrapolated to infinite time [AUC(0-inf)] of LCQ908 for part I of the study	This outcome applies to Part I of study involving mild and moderate hepatic impairment as well as healthy volunteers. Blood will be collected on Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing followed by additional blood draws on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing.	Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing and on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing
Maximum plasma concentration of LCQ908 (Cmax) for Part I of the study	This outcome applies to Part I of study involving mild and moderate hepatic impairment as well as healthy volunteers. Blood will be collected on Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing followed by additional blood draws on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing.	Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing and on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing
The apparent systemic clearance (CL/F) of LCQ908 following extra vascular administration for Part I of the study	This outcome applies to Part I of study involving mild and moderate hepatic impairment as well as healthy volunteers. Blood will be collected on Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing followed by additional blood draws on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing.	Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing and on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing
Area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (AUClast) of LCQ908 for Part II of the study	This outcome applies to Part I of study involving mild and moderate hepatic impairment as well as healthy volunteers. Blood will be collected on Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing followed by additional blood draws on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing.	Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing and on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing
Area under the plasma concentration-time profile from time zero extrapolated to infinite time [AUC(0-inf)] of LCQ908 for Part II of the study	This outcome applies to Part I of study involving mild and moderate hepatic impairment as well as healthy volunteers. Blood will be collected on Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing followed by additional blood draws on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing.	Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing and on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing
Maximum plasma concentration of LCQ908 (Cmax) for Part II of the study	This outcome applies to Part I of study involving mild and moderate hepatic impairment as well as healthy volunteers. Blood will be collected on Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing followed by additional blood draws on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing.	Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing and on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing
The apparent systemic clearance (CL/F) of LCQ908 following extra vascular administration for Part II of the study	This outcome applies to Part I of study involving mild and moderate hepatic impairment as well as healthy volunteers. Blood will be collected on Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing followed by additional blood draws on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing.	Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing and on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with adverse events, serious adverse events and death (for both Part I and Part II)	Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization,cause persistent or significant disability/incapacity, result in congenital abnormalities or birth defects,or are other conditions which in judgment of investigators represent significant hazards.	Day 28
Time to maximum plasma concentration of LCQ908 (Tmax) (for both Part I and Part II)	This outcome applies to Part I and II of the study involving mild and moderate hepatic impairment as well as healthy volunteers for Part I, severe hepatic impairment and healthy volunteers for Part II. Blood will be collected on Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing and on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing	Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing and on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing
The time required for the concentration of the drug to reach half of its original value (T1/2) (for both Part I and Part II)	This outcome applies to Part I and II of the study involving mild and moderate hepatic impairment as well as healthy volunteers for Part I, severe hepatic impairment and healthy volunteers for Part II. Blood will be collected on Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing and on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing	Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing and on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing
The apparent volume of distribution of LCQ908 during the terminal elimination phase following extra vascular administration (Vz/F) (for both Part I and Part II)	This outcome applies to Part I and II of the study involving mild and moderate hepatic impairment as well as healthy volunteers for Part I, severe hepatic impairment and healthy volunteers for Part II. Blood will be collected on Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing and on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing	Day 1 (treatment day) within 60 minutes prior to dosing, then, 1,2,4,6,8,10,12 hours after the dosing and on Days 2, 3, 4, 5, 6,7, 10, 13, 17, 21 and 28 post dosing
LCQ908 protein binding: unbound area under curve (AUCu) of LCQ908 (for both Part I and Part II)	This outcome applies to Part I and II of the study involving mild and moderate hepatic impairment as well as healthy volunteers for Part I, severe hepatic impairment and healthy volunteers for Part II. Blood will be collected 10 and 24 hours post dosing.	10 and 24 hours post dose
LCQ908 protein binding: unbound observed maximum plasma (Cmax) of LCQ908 (for both Part I and Part II)	This outcome applies to Part I and II of the study involving mild and moderate hepatic impairment as well as healthy volunteers for Part I, severe hepatic impairment and healthy volunteers for Part II. Blood will be collected 10 and 24 hours post dosing.	10 and 24 hours
LCQ908 protein binding: unbound apparent systemic clearance from plasma (CL/Fu) following extra vascular administration (for both Part I and Part II)	This outcome applies to Part I and II of the study involving mild and moderate hepatic impairment as well as healthy volunteers for Part I, severe hepatic impairment and healthy volunteers for Part II. Blood will be collected 10 and 24 hours post dosing.	10 and 24 hours

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Hirano M, Meyers D, Golla G, Pal P, Pinot P, Lin T, Majumdar T, Rebello S, Sunkara G, Chen J. Effect of Hepatic Impairment on the Pharmacokinetics of Pradigastat, a Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor. Clin Pharmacokinet. 2015 Jul;54(7):761-70. doi: 10.1007/s40262-015-0235-9.

Helpful Links

• Results for CCLCQ908B2101 can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: May 7, 2012
• First Submitted That Met QC Criteria: May 8, 2012
• First Posted (Estimate): May 9, 2012

Study Record Updates

• Last Update Posted (Actual): December 19, 2020
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: Pharmacokinetics; LCQ908,; Hepatic Impairment,
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases
• Other Study ID Numbers: CLCQ908B2101