Study to Evaluate the Pharmacokinetics of Lemborexant (E2006) and Its Metabolites in Subjects With Mild and Moderate Hepatic Impairment Compared to Healthy Subjects

Hepatic Impairment Clinical Trial

Official title:

An Open-Label, Parallel-Group Study to Evaluate the Pharmacokinetics of Lemborexant (E2006) and Its Metabolites in Subjects With Mild and Moderate Hepatic Impairment Compared to Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03440424
• Other study ID #: E2006-A001-104
• Status: Completed
• Phase: Phase 1
• Start date: January 26, 2018
• Est. completion date: April 23, 2018

Study information

• Verified date: February 2018
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will be conducted to assess the effect of mild and moderate hepatic impairment on the pharmacokinetics (PK) of lemborexant after a single-dose administration.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: April 23, 2018
• Est. primary completion date: April 23, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 79 Years

Eligibility

Inclusion Criteria:

Inclusion Criteria for All Participants:

• Male or female participants, ages 18 to 79, inclusive, at the time of informed consent

• Body Mass Index (BMI) between 18 and 40 kilograms per meters squared, inclusive, at Screening

• Voluntary agreement to provide written informed consent, and the willingness and ability to comply with all aspects of the protocol

• Nonsmokers or smokers who smoke 20 cigarettes or less per day

• For Cohorts A and B: stable (without any change in disease status for at least 60 days prior to study Screening) hepatic impairment conforming to Child-Pugh classification A or B, respectively, and documented by medical history and a physical examination

• For Cohort C: healthy participants matched to participants with hepatic impairment with regard to age (±10 years), sex, and BMI (±20%), and as determined by no clinically significant deviation from normal in medical history, physical examination, electrocardiogram (ECG), and clinical laboratory determinations

Exclusion Criteria:

Exclusion Criteria for All Participants:

• Females who are breastfeeding or pregnant at Screening or Baseline

• Females of childbearing potential who did not use a highly effective method of contraception within 28 days before study entry, or who did not agree to use an approved method of contraception from 28 days before study entry, throughout the entire study period, and for 28 days after study drug discontinuation. Approved (highly effective) methods of contraception for this study included at least one of the following: 1. Total abstinence (if it was their preferred and usual lifestyle); 2. An intrauterine device or intrauterine hormone-releasing system (IUS); 3. A double-barrier method of contraception such as condom plus diaphragm with spermicide;

4. A contraceptive implant; 5. An oral contraceptive (with additional barrier method). Participant must have been on a stable dose of the same oral contraceptive product for at least 28 days before dosing, throughout the study, and for 28 days after study drug discontinuation; 6. Have a vasectomized partner with confirmed azoospermia. (Note: All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).

• Known to be positive for human immunodeficiency virus

• Currently enrolled in another clinical study or used any investigational drug or device within 4 weeks, or 5 times the half-life of the investigational drug (whichever is longer), preceding informed consent

• Receipt of blood products within 4 weeks, or donation of blood within 8 weeks, or donation of plasma within 1 week of dosing until study discharge

• Intake of herbal preparations containing St. John's Wort within 4 weeks prior to dosing until study discharge

• Intake of nutritional supplements (including herbal preparations), foods or beverages that may affect cytochrome P3A enzyme (e.g., alcohol, grapefruit, grapefruit juice, grapefruit-containing beverages, apple or orange juice, vegetables from the mustard green family [e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard] and charbroiled meats) within 1 week before dosing until study discharge

• Intake of beverages, food, or other products that contain caffeine from 24 hours before until 48 hours after dosing with lemborexant

• Engagement in strenuous exercise (e.g., moving large bulky items, bodybuilding) within 2 weeks prior to check-in until study discharge

• History of clinically significant drug or food allergies, or is presently experiencing significant seasonal allergies

• A prolonged QT/corrected QT (QTc) interval (QTc >480 milliseconds) demonstrated on ECG at Screening or Baseline (Day -1)

• Any major surgery within 4 weeks of study drug administration

• Any history of abdominal surgery that may affect pharmacokinetics of lemborexant (e.g., hepatectomy, nephrectomy, digestive organ resection)

• Inability to tolerate oral medication

• Inability to tolerate venous access and/or venipuncture

• Unwilling to abide by the study requirements, or in the opinion of the investigator, is not likely to complete the study

Additional Exclusion Criteria for Hepatically Impaired Participants (Cohorts A and B):

In addition to the Exclusion Criteria listed above for all participants, other standard exclusion criteria for participants with hepatic impairment will be used. These include:

• Any significant acute medical illness (such as new conditions or exacerbation of pre-existing conditions) within 8 weeks of dosing

• Medical conditions which are not adequately and stably controlled on stable doses of medications or which, in the clinical opinion of the Principal Investigator, may interfere with study procedures or participant safety within 4 weeks before dosing (e.g., psychiatric disorders and disorders of the gastrointestinal tract, kidney, respiratory system, endocrine system, hematological system, neurological system, or cardiovascular system, or participants who have a congenital abnormality in metabolism)

• History of esophageal and gastric variceal bleeding within the past 6 months unless the participant has completed a course of endoscopic therapy with the appropriate documentation (e.g., endoscopy report) of successful ablation of esophageal varices; participants with esophageal varices may be included if not bleeding within the past 6 months or have been treated adequately by ablation therapy, as specified above.

• Spontaneous bacterial peritonitis within 3 months of dosing

• Treatment with plasmapheresis within 6 months of dosing

• Primarily cholestatic liver diseases (e.g., primary biliary cirrhosis or primary sclerosing cholangitis)

• Current or recent (within 3 months prior to Screening) history of significant gastrointestinal disease other than that secondary to hepatic impairment

• Autoimmune liver disease

• Active alcoholic hepatitis determined either clinically or by histology

• History of hepatoma or metastatic disease of the liver

• Presence of severe ascites or edema

• Presence of hepatopulmonary syndrome or hydrothorax, or hepatorenal syndrome

• Known significant bleeding diathesis that could preclude multiple venipunctures (international normalization ratio >2.5)

• Creatinine clearance <60 milliliters per minute at Screening or Baseline as calculated using Cockroft and Gault Equation

• The participant's standard therapy/concomitant medication for diseases related to cirrhosis has not remained stable/unchanged for at least 14 days before the first dose of study drug

• History of drug or alcohol dependency or abuse within 4 weeks prior to Screening, or those who have a positive urine drug test or breath alcohol test at Screening or Baseline unless a prescribed medication for the underlying condition is the cause of the positive urine screen

Additional Exclusion Criteria for Healthy Participants (Cohort C):

In addition to the Exclusion Criteria listed above for all participants, other standard exclusion criteria for healthy participants in Phase 1 studies will be used. These include:

• Presence of active liver disease, or acute liver injury, as indicated by (1) an abnormal liver function test, or (2) clinical or laboratory signs of active viral hepatitis (including B and C, as demonstrated by positive serology at Screening)

• Clinically significant illness, within 4 weeks prior to dosing, that requires medical treatment or may influence the outcome of the study; e.g., psychiatric disorders and disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, or cardiovascular system, or participants who have a congenital abnormality in metabolism

• Any abnormal finding based on physical examination, assessment of vital signs, ECG, or laboratory test results that require treatment or clinical follow-up based on the investigator's opinion

• History of drug or alcohol use disorder within the 2 years prior to Screening, or those who have a positive urine drug test or breathalyzer alcohol test at Screening or Baseline

• Use of any prescription drugs within 4 weeks prior to dosing until study discharge

• Intake of any over-the-counter medications within 2 weeks prior to dosing until study discharge

Related Conditions & MeSH terms

• Hepatic Impairment
• Liver Diseases

Intervention

Drug:
• Lemborexant
oral tablet

Locations

Country	Name	City	State
United States	Clinical Pharmacology of Miami, LLC	Miami	Florida
United States	Orlando Clinical Research Center	Orlando	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Eisai Inc.	Purdue Pharma LP

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cmax: Maximum Plasma Concentration of Lemborexant	Blood samples were analyzed for the amount of lemborexant in the plasma. Plasma concentration-time data were measured by validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Plasma pharmacokinetic (PK) data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Primary	AUC(0-8 Hours): Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours Postdose of Lemoborexant	Blood samples were analyzed for the amount of lemborexant in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. AUC(0-8 hours) was calculated by the linear-up log-down trapezoidal method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Primary	AUC(0-72 Hours): Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours Postdose of Lemoborexant	Blood samples were analyzed for the amount of lemborexant in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. AUC(0-72 hours) was calculated by the linear-up log-down trapezoidal method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Primary	AUC(0-t Hours): Area Under Plasma Concentration Versus Time Curve From Time Zero to Time of Last Quantifiable Concentration of Lemborexant	Blood samples were analyzed for the amount of lemborexant in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. AUC(0-t hours) was calculated by the linear-up log-down trapezoidal method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Primary	AUC(0-inf): Area Under Plasma Concentration Versus Time Curve From Time Zero to Infinity of Lemborexant	Blood samples were analyzed for the amount of lemborexant in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. AUC(0-inf) was calculated by the linear-up log-down trapezoidal method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Secondary	AUCu: AUC(0-inf) Values Adjusted by Unbound Fraction in Plasma of Lemborexant	AUCu was defined as the AUC(0-inf) adjusted by unbound fraction in plasma, and calculated by multiplying the value of AUC(0-inf) with plasma protein unbound fraction (fu). Blood samples were analyzed for the amount of lemborexant in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. AUCu was calculated by the linear-up log-down trapezoidal method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Secondary	Cmax: Maximum Plasma Concentration of Lemborexant's Metabolites M4, M9, and M10	Blood samples were analyzed for the amount of lemborexant's metabolites (M4, M9, M10) in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Secondary	Tmax: Time to Reach Maximum Plasma Concentration of Lemborexant and Its Metabolites M4, M9, M10	Blood samples were analyzed for the amount of lemborexant and its metabolites (M4, M9, M10) in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Secondary	AUC(0-8 Hours): Area Under Plasma Concentration Versus Time Curve From Time Zero to 8 Hours Postdose of Lemborexant's Metabolites M4, M9, and M10	Blood samples were analyzed for the amount of lemborexant's metabolites (M4, M9, M10) in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. AUC(0-8 hours) was calculated by the linear-up log-down trapezoidal method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Secondary	AUC(0-72 Hours): Area Under Plasma Concentration Versus Time Curve From Time Zero to 72 Hours Postdose of Lemborexant's Metabolites M4, M9, and M10	Blood samples were analyzed for the amount of lemborexant's metabolites (M4, M9, M10) in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. AUC(0-72 hours) was calculated by the linear-up log-down trapezoidal method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Secondary	AUC(0-t Hours): Area Under Plasma Concentration Versus Time Curve From Time Zero to t Hours Postdose of Lemborexant's Metabolites M4, M9, and M10	Blood samples were analyzed for the amount of lemborexant's metabolites (M4, M9, M10) in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. AUC(0-t hours) was calculated by the linear-up log-down trapezoidal method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Secondary	AUC(0-inf): Area Under Plasma Concentration Versus Time Curve From Time Zero to Inf Hours Postdose of Lemborexant's Metabolites M4, M9, and M10	Blood samples were analyzed for the amount of lemborexant's metabolites (M4, M9, M10) in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. AUC(0-inf) was calculated by the linear-up log-down trapezoidal method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Secondary	T1/2: Terminal Plasma Phase Half-life of Lemborexant and Its Metabolites M4, M9, M10	Terminal plasma half-life is the time required for plasma/blood concentration to decrease by 50%. This is not the time required to eliminate half the administered dose. Blood samples were analyzed for the amount of lemborexant and its metabolites (M4, M9, M10) in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Secondary	CL/F: Apparent Total Body Clearance of Lemborexant	CL/F is the clearance for parent lemborexant only and was calculated as Dose/[AUC 0-inf]. Blood samples were analyzed for the amount of lemborexant in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Secondary	Vz/F: Apparent Volume of Distribution of Lemborexant	The apparent volume of distribution gives information about amount of lemborexant distributed in body tissue rather than the blood/plasma. Vz/F for parent lemborexant only was calculated as Dose/(AUC0-inf multiplied by elimination rate constant[?z]). Area under the plasma concentration-time curve from time zero to infinity, calculated(AUC0-inf) as AUC0-t + AUCextra. AUCextra represents an extrapolated value obtained by Clast/?z, where Clast: plasma concentration at last sampling time point at which measured plasma concentration is at or above LLQ. ?z is the elimination rate constant. Elimination rate constant obtained from linear regression of terminal phase of log transformed concentration-time data. A minimum of three points is required to calculate ?z. Blood samples were analyzed for amount of lemborexant in plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Secondary	MPR: Metabolite-to-Parent Ratios of AUC(0-inf) for Lemborexant's Metabolites M4, M9, and M10	The MPR is the ratio of AUC(0-inf) of the individual lemborexant metabolites (M4, M9, M10) to AUC(0-inf) of lemborexant, corrected for molecular weights. Blood samples were analyzed for the amount of lemborexant metabolites in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Secondary	fu: Plasma Protein Unbound Fraction of Lemborexant and Its Metabolites M4, M9, and M10	Unbound fraction of drug in plasma was calculated as 100 percent (%) - mean percent of lemborexant and its metabolites M4, M9, and M10 bound to plasma protein for each participant. Blood samples were analyzed for the amount of lemborexant and its metabolites (M4, M9, M10) in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose
Secondary	CLu/F: Apparent Clearance Relative to the Unbound Plasma Concentration Based on AUCu of Lemborexant	Unbound fraction of drug in plasma was calculated as 100% - mean percent of lemborexant bound to plasma protein for each participant. Blood samples were analyzed for the amount of lemborexant in the plasma. Plasma concentration-time data were measured by validated LC-MS/MS method. Plasma PK data were analyzed using a non-compartmental method of analysis.	Day 1: Predose, 0.5 up to 312 hours postdose