Study to Evaluate the Pharmacokinetics of Lemborexant (E2... | NCT03440424

NCT03440424

Status Module

Sponsor/Collaborators Module

Name	Class
Purdue Pharma LP	INDUSTRY

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Experimental	Participants with mild hepatic impairment will receive a single 10 milligram (mg) dose (1 × 10 mg lemborexant [E2006] tablet) in the morning with 240 milliliters (mL) of water following an overnight fast of at least 10 hours.	Drug: Lemborexant
Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)	Experimental	Participants with moderate hepatic impairment will receive a single 10 mg dose (1 × 10 mg lemborexant [E2006] tablet) in the morning with 240 mL of water following an overnight fast of at least 10 hours.	Drug: Lemborexant
Cohort C: Healthy Participants (Control)	Experimental	Healthy participants matched to participants with hepatic impairment in Cohorts A and B (matched with regards to age, sex, body mass index [BMI]) will receive a single 10 mg dose (1 × 10 mg lemborexant [E2006] tablet) in the morning with 240 mL of water following an overnight fast of at least 10 hours.	Drug: Lemborexant

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Lemborexant	Drug	oral tablet	Cohort A: Mild Hepatic Impairment (Child Pugh Class A) Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) Cohort C: Healthy Participants (Control)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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
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
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
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
AUC(0-inf): Area Under Plasma Concentration Versus Time Curve From Time Zero to Infinity of Lemborexant

Secondary Outcomes

Measure	Description	Time Frame
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.

Eligibility Module

Eligibility Criteria

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

Contacts/Locations Module

Facility	Status	City	State	ZIP	Country	Contacts
Clinical Pharmacology of Miami, LLC		Miami	Florida	33014	United States
Orlando Clinical Research Center

References Module

No data available

No data is available for this block.

IPD Sharing Statement Module

No data available

No data is available for this block.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 milligrams (mg) administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Feb 28, 2018	Jan 30, 2020

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

No data available

No data is available for this block.

Intervention Browse Module

Masking Info

The Safety Analysis Set (SAS) was the group of participants who were dosed with the test drug and had atleast 1 postdose safety assessment.

Arm/Group Information

ID	Title	Description
BG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
BG001	Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)	Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
BG002	Cohort C: Healthy Participants (Control)	Healthy participants matched to participants with hepatic impairment in Cohorts A and B (with regards to age, sex, BMI) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period.
BG003	Total	Total of all reporting groups

Units	Counts
Participants	BG0008 BG0018 BG0028 BG00324

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00057.0± 10.5 BG00161.4± 5.7 BG00256.8± 8.3 BG003

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG0002 BG0012 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG0005 BG0012 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000 BG0010 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter.

Posted

Geometric Mean

Geometric Coefficient of Variation

nanogram per milliliter (ng/mL)

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001	Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)	Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG002	Cohort C: Healthy Participants (Control)	Healthy participants matched to participants with hepatic impairment in Cohorts A and B (with regards to age, sex, BMI) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period.

Units	Counts
Participants	OG0008 OG0018 OG0028

Title

Denominators

Categories

Title	Measurements
	OG00062.9± 34.9 OG00148.7± 37.7 OG00239.8± 31.1

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002						Percent ratio of geometric mean	157.86			2-Sided	90	118.18	210.87			Percent ratio of geometric mean was calculated by dividing the geometric mean of test by geometric mean of reference, then multiplying the value by 100.		Other
OG001 OG002

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter.

Posted

Geometric Mean

Geometric Coefficient of Variation

hour nanogram per milliliter (h*ng/mL)

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001	Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter.

Posted

Geometric Mean

Geometric Coefficient of Variation

h*ng/mL

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001	Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter.

Posted

Geometric Mean

Geometric Coefficient of Variation

h*ng/mL

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001	Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter. Here "Overall number of participants analyzed" signifies the participants who were evaluable for this outcome measure.

Posted

Geometric Mean

Geometric Coefficient of Variation

h*ng/mL

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001	Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

h*ng/mL

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001	Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)	Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter.

Posted

Median

Full Range

hours

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001	Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)	Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter.

Posted

Geometric Mean

Geometric Coefficient of Variation

h*ng/mL

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001	Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter.

Posted

Geometric Mean

Geometric Coefficient of Variation

h*ng/mL

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001	Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter.

Posted

Geometric Mean

Geometric Coefficient of Variation

h*ng/mL

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001	Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter. Here "Number analyzed" signifies participants who were evaluable for this outcome measure for different metabolites M4, M9, and M10.

Posted

Geometric Mean

Geometric Coefficient of Variation

h*ng/mL

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001

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.

Posted

Median

Full Range

hrs

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter. Here "Overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Posted

Geometric Mean

Geometric Coefficient of Variation

Liter per hour (L/hr)

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001	Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)

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[λz]). 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/λz, where Clast: plasma concentration at last sampling time point at which measured plasma concentration is at or above LLQ. λz 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 λz. 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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter. Here "Overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Posted

Geometric Mean

Geometric Coefficient of Variation

Liter (L)

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter. Here "Number analyzed" signifies participants who were evaluable for the outcome measure for each metabolite (M4, M9, and M10).

Posted

Geometric Mean

Geometric Coefficient of Variation

ratio

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter.

Posted

Geometric Mean

Geometric Coefficient of Variation

% (percent) unbound

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001	Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)

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.

The PK Analysis Set was the group of participants who were dosed with the test drug and had sufficient PK data to derive at least 1 PK parameter. Here "Overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Posted

Geometric Mean

Geometric Coefficient of Variation

L/h

Day 1: Predose, 0.5 up to 312 hours postdose

ID	Title	Description
OG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
OG001

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Cohort A: Mild Hepatic Impairment (Child Pugh Class A)	Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.	8	8	7	8
EG001	Cohort B: Moderate Hepatic Impairment (Child Pugh Class B)	Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.	8	8	6	8
EG002	Cohort C: Healthy Participants (Control)	Healthy participants matched to participants with hepatic impairment in Cohorts A and B (with regards to age, sex, BMI) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period.	8	8	7	8

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Dry mouth	Gastrointestinal disorders	MedDRA (20.1)	Systematic Assessment	EG0000 affected8 at risk EG0011 affected8 at risk EG0020 affected8 at risk
Chills	General disorders	MedDRA (20.1)	Systematic Assessment	EG0000 affected8 at risk EG0011 affected8 at risk EG0020 affected8 at risk
Headache	Nervous system disorders	MedDRA (20.1)	Systematic Assessment	EG0000 affected8 at risk EG0011 affected8 at risk EG0020 affected8 at risk
Somnolence	Nervous system disorders	MedDRA (20.1)	Systematic Assessment	EG0007 affected8 at risk EG0015 affected8 at risk EG0027 affected8 at risk

ID	Term
C000634104	lemborexant

Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received lemborexant 10 mg administered as a tablet, orally in the morning on Day 1 of the 14-day Treatment Period. The Child-Pugh Score is a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.

OG001102(75.6 to 112)

OG00268.1(16.7 to 95.3)

OG00188.4(70.0 to 126)

OG00249.7(14.0 to 72.7)

OG00196.8(67.4 to 118)

OG00269.3(32.3 to 90.7)