Hepatic Impairment
Conditions
Keywords
mild hepatic impairment, moderate hepatic impairment, lemborexant, healthy participants, metabolites, E2006, pharmacokinetics
Brief 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.
Interventions
DRUGLemborexant
oral tablet
Sponsors
Purdue Pharma LP
Eisai Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax: Maximum Plasma Concentration of Lemborexant | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| AUC(0-8 Hours): Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours Postdose of Lemoborexant | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| AUC(0-72 Hours): Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours Postdose of Lemoborexant | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| AUC(0-t Hours): Area Under Plasma Concentration Versus Time Curve From Time Zero to Time of Last Quantifiable Concentration of Lemborexant | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| AUC(0-inf): Area Under Plasma Concentration Versus Time Curve From Time Zero to Infinity of Lemborexant | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| 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 | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| T1/2: Terminal Plasma Phase Half-life of Lemborexant and Its Metabolites M4, M9, M10 | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| CL/F: Apparent Total Body Clearance of Lemborexant | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| AUCu: AUC(0-inf) Values Adjusted by Unbound Fraction in Plasma of Lemborexant | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| MPR: Metabolite-to-Parent Ratios of AUC(0-inf) for Lemborexant's Metabolites M4, M9, and M10 | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| fu: Plasma Protein Unbound Fraction of Lemborexant and Its Metabolites M4, M9, and M10 | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| CLu/F: Apparent Clearance Relative to the Unbound Plasma Concentration Based on AUCu of Lemborexant | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| Vz/F: Apparent Volume of Distribution of Lemborexant | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| Cmax: Maximum Plasma Concentration of Lemborexant's Metabolites M4, M9, and M10 | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| Tmax: Time to Reach Maximum Plasma Concentration of Lemborexant and Its Metabolites M4, M9, M10 | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| 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 | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
| 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 | Day 1: Predose, 0.5 up to 312 hours postdose | 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. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 2 investigative sites in the United States from 26 January 2018 to 23 April 2018.
Pre-assignment details
A total of 28 participants were screened, of which 4 were screen failures, and 24 were enrolled and received the study treatment.
Participants by arm
| Arm | Count |
|---|---|
| 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 |
| 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 |
| 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 |
| Total | 24 |
Baseline characteristics
| Characteristic | Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | Total | Cohort C: Healthy Participants (Control) |
|---|---|---|---|---|
| Age, Continuous | 61.4 years STANDARD_DEVIATION 5.7 | 57.0 years STANDARD_DEVIATION 10.5 | 58.4 years STANDARD_DEVIATION 8.3 | 56.8 years STANDARD_DEVIATION 8.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 12 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 3 Participants | 12 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 8 Participants | 24 Participants | 8 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 7 Participants | 3 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 17 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 7 / 8 | 6 / 8 | 7 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | AUC(0-72 Hours): Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours Postdose of Lemoborexant | 383 h*ng/mL | Geometric Coefficient of Variation 46.1 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | AUC(0-72 Hours): Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours Postdose of Lemoborexant | 352 h*ng/mL | Geometric Coefficient of Variation 13 |
| Cohort C: Healthy Participants (Control) | AUC(0-72 Hours): Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours Postdose of Lemoborexant | 306 h*ng/mL | Geometric Coefficient of Variation 25 |
90% CI: [96.76, 162.16]
90% CI: [88.98, 149.13]
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | AUC(0-8 Hours): Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours Postdose of Lemoborexant | 163 hour nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 32.8 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | AUC(0-8 Hours): Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours Postdose of Lemoborexant | 138 hour nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 13.8 |
| Cohort C: Healthy Participants (Control) | AUC(0-8 Hours): Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours Postdose of Lemoborexant | 133 hour nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 25.1 |
90% CI: [98.95, 151.17]
90% CI: [83.53, 127.61]
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | AUC(0-inf): Area Under Plasma Concentration Versus Time Curve From Time Zero to Infinity of Lemborexant | 567 h*ng/mL | Geometric Coefficient of Variation 52 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | AUC(0-inf): Area Under Plasma Concentration Versus Time Curve From Time Zero to Infinity of Lemborexant | 696 h*ng/mL | Geometric Coefficient of Variation 34.6 |
| Cohort C: Healthy Participants (Control) | AUC(0-inf): Area Under Plasma Concentration Versus Time Curve From Time Zero to Infinity of Lemborexant | 453 h*ng/mL | Geometric Coefficient of Variation 33.9 |
90% CI: [87.96, 177.74]
90% CI: [106.39, 221.66]
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | AUC(0-t Hours): Area Under Plasma Concentration Versus Time Curve From Time Zero to Time of Last Quantifiable Concentration of Lemborexant | 574 h*ng/mL | Geometric Coefficient of Variation 50.7 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | AUC(0-t Hours): Area Under Plasma Concentration Versus Time Curve From Time Zero to Time of Last Quantifiable Concentration of Lemborexant | 651 h*ng/mL | Geometric Coefficient of Variation 25.6 |
| Cohort C: Healthy Participants (Control) | AUC(0-t Hours): Area Under Plasma Concentration Versus Time Curve From Time Zero to Time of Last Quantifiable Concentration of Lemborexant | 435 h*ng/mL | Geometric Coefficient of Variation 33.2 |
90% CI: [96.46, 180.4]
90% CI: [109.34, 204.47]
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | Cmax: Maximum Plasma Concentration of Lemborexant | 62.9 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 34.9 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | Cmax: Maximum Plasma Concentration of Lemborexant | 48.7 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 37.7 |
| Cohort C: Healthy Participants (Control) | Cmax: Maximum Plasma Concentration of Lemborexant | 39.8 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 31.1 |
90% CI: [118.18, 210.87]
90% CI: [91.49, 163.24]
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | 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 | M9 | 52.1 h*ng/mL | Geometric Coefficient of Variation 29.1 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | 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 | M4 | 153 h*ng/mL | Geometric Coefficient of Variation 36.7 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | 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 | M10 | 167 h*ng/mL | Geometric Coefficient of Variation 41.3 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | 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 | M9 | 52.5 h*ng/mL | Geometric Coefficient of Variation 18.9 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | 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 | M4 | 123 h*ng/mL | Geometric Coefficient of Variation 19.5 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | 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 | M10 | 130 h*ng/mL | Geometric Coefficient of Variation 23 |
| Cohort C: Healthy Participants (Control) | 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 | M4 | 144 h*ng/mL | Geometric Coefficient of Variation 26.8 |
| Cohort C: Healthy Participants (Control) | 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 | M10 | 175 h*ng/mL | Geometric Coefficient of Variation 35.3 |
| Cohort C: Healthy Participants (Control) | 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 | M9 | 69.1 h*ng/mL | Geometric Coefficient of Variation 18 |
Comparison: M4 metabolite90% CI: [83.95, 135.62]
Comparison: M4 metabolite90% CI: [67.41, 108.9]
Comparison: M9 metabolite90% CI: [62.28, 91.31]
Comparison: M9 metabolite90% CI: [62.76, 92.02]
Comparison: M10 metabolite90% CI: [71.92, 126.94]
Comparison: M10 metabolite90% CI: [56.06, 98.94]
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | 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 | M9 | 17.5 h*ng/mL | Geometric Coefficient of Variation 29.2 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | 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 | M4 | 44.2 h*ng/mL | Geometric Coefficient of Variation 27.2 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | 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 | M10 | 21.4 h*ng/mL | Geometric Coefficient of Variation 40.7 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | 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 | M9 | 14.0 h*ng/mL | Geometric Coefficient of Variation 31.1 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | 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 | M4 | 31.0 h*ng/mL | Geometric Coefficient of Variation 34.4 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | 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 | M10 | 16.3 h*ng/mL | Geometric Coefficient of Variation 35.1 |
| Cohort C: Healthy Participants (Control) | 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 | M4 | 44.6 h*ng/mL | Geometric Coefficient of Variation 28.6 |
| Cohort C: Healthy Participants (Control) | 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 | M10 | 22.6 h*ng/mL | Geometric Coefficient of Variation 40.4 |
| Cohort C: Healthy Participants (Control) | 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 | M9 | 22.2 h*ng/mL | Geometric Coefficient of Variation 19.3 |
Comparison: M4 metabolite90% CI: [76.91, 127.81]
Comparison: M4 metabolite90% CI: [54.03, 89.79]
Comparison: M9 metabolite90% CI: [62.88, 99.21]
Comparison: M9 metabolite90% CI: [50.31, 79.38]
Comparison: M10 metabolite90% CI: [68.5, 130.51]
Comparison: M10 metabolite90% CI: [52.03, 99.12]
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | 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 | M9 | 72.6 h*ng/mL | Geometric Coefficient of Variation 34.7 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | 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 | M4 | 220 h*ng/mL | Geometric Coefficient of Variation 50.3 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | 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 | M10 | 304 h*ng/mL | Geometric Coefficient of Variation 27.7 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | 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 | M9 | 108 h*ng/mL | Geometric Coefficient of Variation 21.6 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | 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 | M4 | 223 h*ng/mL | Geometric Coefficient of Variation 21.3 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | 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 | M10 | 332 h*ng/mL | Geometric Coefficient of Variation 17.9 |
| Cohort C: Healthy Participants (Control) | 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 | M4 | 191 h*ng/mL | Geometric Coefficient of Variation 31.6 |
| Cohort C: Healthy Participants (Control) | 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 | M10 | 320 h*ng/mL | Geometric Coefficient of Variation 41.9 |
| Cohort C: Healthy Participants (Control) | 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 | M9 | 92.5 h*ng/mL | Geometric Coefficient of Variation 23.5 |
Comparison: M4 metabolite90% CI: [83.51, 159.42]
Comparison: M4 metabolite90% CI: [84.66, 161.62]
Comparison: M9 metabolite90% CI: [61.06, 100.81]
Comparison: M9 metabolite90% CI: [89.95, 151.56]
Comparison: M10 metabolite90% CI: [70.31, 128.28]
Comparison: M10 metabolite90% CI: [75.43, 142.28]
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | 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 | M4 | 208 h*ng/mL | Geometric Coefficient of Variation 45.8 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | 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 | M9 | 69.7 h*ng/mL | Geometric Coefficient of Variation 34.9 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | 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 | M10 | 334 h*ng/mL | Geometric Coefficient of Variation 42.8 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | 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 | M10 | 321 h*ng/mL | Geometric Coefficient of Variation 19.9 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | 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 | M9 | 89.6 h*ng/mL | Geometric Coefficient of Variation 23 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | 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 | M4 | 191 h*ng/mL | Geometric Coefficient of Variation 20.6 |
| Cohort C: Healthy Participants (Control) | 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 | M4 | 184 h*ng/mL | Geometric Coefficient of Variation 31.3 |
| Cohort C: Healthy Participants (Control) | 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 | M9 | 88.7 h*ng/mL | Geometric Coefficient of Variation 21.4 |
| Cohort C: Healthy Participants (Control) | 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 | M10 | 305 h*ng/mL | Geometric Coefficient of Variation 41.5 |
Comparison: M4 metabolite90% CI: [85.16, 150.05]
Comparison: M4 metabolite90% CI: [78.16, 137.7]
Comparison: M9 metabolite90% CI: [62.57, 98.78]
Comparison: M9 metabolite90% CI: [80.38, 126.9]
Comparison: M10 metabolite90% CI: [81.07, 147.88]
Comparison: M10 metabolite90% CI: [77.89, 142.08]
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | AUCu: AUC(0-inf) Values Adjusted by Unbound Fraction in Plasma of Lemborexant | 34.9 h*ng/mL | Geometric Coefficient of Variation 52.6 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | AUCu: AUC(0-inf) Values Adjusted by Unbound Fraction in Plasma of Lemborexant | 45.1 h*ng/mL | Geometric Coefficient of Variation 42.6 |
| Cohort C: Healthy Participants (Control) | AUCu: AUC(0-inf) Values Adjusted by Unbound Fraction in Plasma of Lemborexant | 27.1 h*ng/mL | Geometric Coefficient of Variation 36.8 |
90% CI: [88.35, 188.02]
90% CI: [112.31, 246.99]
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | CL/F: Apparent Total Body Clearance of Lemborexant | 17.6 Liter per hour (L/hr) | Geometric Coefficient of Variation 52 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | CL/F: Apparent Total Body Clearance of Lemborexant | 14.4 Liter per hour (L/hr) | Geometric Coefficient of Variation 34.6 |
| Cohort C: Healthy Participants (Control) | CL/F: Apparent Total Body Clearance of Lemborexant | 22.1 Liter per hour (L/hr) | Geometric Coefficient of Variation 33.9 |
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | CLu/F: Apparent Clearance Relative to the Unbound Plasma Concentration Based on AUCu of Lemborexant | 287 L/h | Geometric Coefficient of Variation 52.6 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | CLu/F: Apparent Clearance Relative to the Unbound Plasma Concentration Based on AUCu of Lemborexant | 222 L/h | Geometric Coefficient of Variation 42.6 |
| Cohort C: Healthy Participants (Control) | CLu/F: Apparent Clearance Relative to the Unbound Plasma Concentration Based on AUCu of Lemborexant | 370 L/h | Geometric Coefficient of Variation 36.8 |
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | Cmax: Maximum Plasma Concentration of Lemborexant's Metabolites M4, M9, and M10 | M9 | 4.49 ng/mL | Geometric Coefficient of Variation 45.1 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | Cmax: Maximum Plasma Concentration of Lemborexant's Metabolites M4, M9, and M10 | M4 | 7.73 ng/mL | Geometric Coefficient of Variation 36.4 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | Cmax: Maximum Plasma Concentration of Lemborexant's Metabolites M4, M9, and M10 | M10 | 3.52 ng/mL | Geometric Coefficient of Variation 44.4 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | Cmax: Maximum Plasma Concentration of Lemborexant's Metabolites M4, M9, and M10 | M9 | 3.50 ng/mL | Geometric Coefficient of Variation 46.4 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | Cmax: Maximum Plasma Concentration of Lemborexant's Metabolites M4, M9, and M10 | M4 | 5.74 ng/mL | Geometric Coefficient of Variation 46.7 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | Cmax: Maximum Plasma Concentration of Lemborexant's Metabolites M4, M9, and M10 | M10 | 2.84 ng/mL | Geometric Coefficient of Variation 38.4 |
| Cohort C: Healthy Participants (Control) | Cmax: Maximum Plasma Concentration of Lemborexant's Metabolites M4, M9, and M10 | M4 | 7.97 ng/mL | Geometric Coefficient of Variation 33 |
| Cohort C: Healthy Participants (Control) | Cmax: Maximum Plasma Concentration of Lemborexant's Metabolites M4, M9, and M10 | M10 | 3.71 ng/mL | Geometric Coefficient of Variation 34.8 |
| Cohort C: Healthy Participants (Control) | Cmax: Maximum Plasma Concentration of Lemborexant's Metabolites M4, M9, and M10 | M9 | 5.33 ng/mL | Geometric Coefficient of Variation 28.9 |
Comparison: M9 metabolite90% CI: [46.89, 92.05]
Comparison: M10 metabolite90% CI: [68.37, 131.3]
Comparison: M10 metabolite90% CI: [55.24, 106.09]
Comparison: M4 metabolite90% CI: [70.15, 134.06]
Comparison: M4 metabolite90% CI: [52.12, 99.6]
Comparison: M9 metabolite90% CI: [60.21, 118.19]
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | fu: Plasma Protein Unbound Fraction of Lemborexant and Its Metabolites M4, M9, and M10 | Lemborexant | 0.0630 % (percent) unbound | Geometric Coefficient of Variation 14.2 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | fu: Plasma Protein Unbound Fraction of Lemborexant and Its Metabolites M4, M9, and M10 | M4 | 0.247 % (percent) unbound | Geometric Coefficient of Variation 7.77 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | fu: Plasma Protein Unbound Fraction of Lemborexant and Its Metabolites M4, M9, and M10 | M9 | 0.146 % (percent) unbound | Geometric Coefficient of Variation 14 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | fu: Plasma Protein Unbound Fraction of Lemborexant and Its Metabolites M4, M9, and M10 | M10 | 0.0765 % (percent) unbound | Geometric Coefficient of Variation 15.4 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | fu: Plasma Protein Unbound Fraction of Lemborexant and Its Metabolites M4, M9, and M10 | M10 | 0.0754 % (percent) unbound | Geometric Coefficient of Variation 16.6 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | fu: Plasma Protein Unbound Fraction of Lemborexant and Its Metabolites M4, M9, and M10 | Lemborexant | 0.0650 % (percent) unbound | Geometric Coefficient of Variation 11.4 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | fu: Plasma Protein Unbound Fraction of Lemborexant and Its Metabolites M4, M9, and M10 | M9 | 0.142 % (percent) unbound | Geometric Coefficient of Variation 9.61 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | fu: Plasma Protein Unbound Fraction of Lemborexant and Its Metabolites M4, M9, and M10 | M4 | 0.247 % (percent) unbound | Geometric Coefficient of Variation 12.4 |
| Cohort C: Healthy Participants (Control) | fu: Plasma Protein Unbound Fraction of Lemborexant and Its Metabolites M4, M9, and M10 | M10 | 0.0669 % (percent) unbound | Geometric Coefficient of Variation 20.2 |
| Cohort C: Healthy Participants (Control) | fu: Plasma Protein Unbound Fraction of Lemborexant and Its Metabolites M4, M9, and M10 | M4 | 0.230 % (percent) unbound | Geometric Coefficient of Variation 12.8 |
| Cohort C: Healthy Participants (Control) | fu: Plasma Protein Unbound Fraction of Lemborexant and Its Metabolites M4, M9, and M10 | M9 | 0.136 % (percent) unbound | Geometric Coefficient of Variation 15.8 |
| Cohort C: Healthy Participants (Control) | fu: Plasma Protein Unbound Fraction of Lemborexant and Its Metabolites M4, M9, and M10 | Lemborexant | 0.0597 % (percent) unbound | Geometric Coefficient of Variation 15.3 |
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | MPR: Metabolite-to-Parent Ratios of AUC(0-inf) for Lemborexant's Metabolites M4, M9, and M10 | M9 | 0.123 ratio | Geometric Coefficient of Variation 19 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | MPR: Metabolite-to-Parent Ratios of AUC(0-inf) for Lemborexant's Metabolites M4, M9, and M10 | M4 | 0.343 ratio | Geometric Coefficient of Variation 2.9 |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | MPR: Metabolite-to-Parent Ratios of AUC(0-inf) for Lemborexant's Metabolites M4, M9, and M10 | M10 | 0.600 ratio | Geometric Coefficient of Variation 15.3 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | MPR: Metabolite-to-Parent Ratios of AUC(0-inf) for Lemborexant's Metabolites M4, M9, and M10 | M9 | 0.144 ratio | Geometric Coefficient of Variation 17.4 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | MPR: Metabolite-to-Parent Ratios of AUC(0-inf) for Lemborexant's Metabolites M4, M9, and M10 | M4 | 0.289 ratio | Geometric Coefficient of Variation 23.4 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | MPR: Metabolite-to-Parent Ratios of AUC(0-inf) for Lemborexant's Metabolites M4, M9, and M10 | M10 | 0.502 ratio | Geometric Coefficient of Variation 20.4 |
| Cohort C: Healthy Participants (Control) | MPR: Metabolite-to-Parent Ratios of AUC(0-inf) for Lemborexant's Metabolites M4, M9, and M10 | M4 | 0.405 ratio | Geometric Coefficient of Variation 11.5 |
| Cohort C: Healthy Participants (Control) | MPR: Metabolite-to-Parent Ratios of AUC(0-inf) for Lemborexant's Metabolites M4, M9, and M10 | M10 | 0.680 ratio | Geometric Coefficient of Variation 18.9 |
| Cohort C: Healthy Participants (Control) | MPR: Metabolite-to-Parent Ratios of AUC(0-inf) for Lemborexant's Metabolites M4, M9, and M10 | M9 | 0.198 ratio | Geometric Coefficient of Variation 22 |
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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 lemborexant and its metabolites (M4, M9, and M10).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | T1/2: Terminal Plasma Phase Half-life of Lemborexant and Its Metabolites M4, M9, M10 | Lemborexant | 92.7 hrs |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | T1/2: Terminal Plasma Phase Half-life of Lemborexant and Its Metabolites M4, M9, M10 | M4 | 69.2 hrs |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | T1/2: Terminal Plasma Phase Half-life of Lemborexant and Its Metabolites M4, M9, M10 | M9 | 49.0 hrs |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | T1/2: Terminal Plasma Phase Half-life of Lemborexant and Its Metabolites M4, M9, M10 | M10 | 71.0 hrs |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | T1/2: Terminal Plasma Phase Half-life of Lemborexant and Its Metabolites M4, M9, M10 | M10 | 96.8 hrs |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | T1/2: Terminal Plasma Phase Half-life of Lemborexant and Its Metabolites M4, M9, M10 | Lemborexant | 115 hrs |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | T1/2: Terminal Plasma Phase Half-life of Lemborexant and Its Metabolites M4, M9, M10 | M9 | 88.4 hrs |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | T1/2: Terminal Plasma Phase Half-life of Lemborexant and Its Metabolites M4, M9, M10 | M4 | 102 hrs |
| Cohort C: Healthy Participants (Control) | T1/2: Terminal Plasma Phase Half-life of Lemborexant and Its Metabolites M4, M9, M10 | M10 | 69.3 hrs |
| Cohort C: Healthy Participants (Control) | T1/2: Terminal Plasma Phase Half-life of Lemborexant and Its Metabolites M4, M9, M10 | M4 | 68.1 hrs |
| Cohort C: Healthy Participants (Control) | T1/2: Terminal Plasma Phase Half-life of Lemborexant and Its Metabolites M4, M9, M10 | M9 | 49.7 hrs |
| Cohort C: Healthy Participants (Control) | T1/2: Terminal Plasma Phase Half-life of Lemborexant and Its Metabolites M4, M9, M10 | Lemborexant | 71.1 hrs |
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | Tmax: Time to Reach Maximum Plasma Concentration of Lemborexant and Its Metabolites M4, M9, M10 | Lemborexant | 1.00 hours |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | Tmax: Time to Reach Maximum Plasma Concentration of Lemborexant and Its Metabolites M4, M9, M10 | M4 | 1.75 hours |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | Tmax: Time to Reach Maximum Plasma Concentration of Lemborexant and Its Metabolites M4, M9, M10 | M9 | 1.25 hours |
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | Tmax: Time to Reach Maximum Plasma Concentration of Lemborexant and Its Metabolites M4, M9, M10 | M10 | 4.00 hours |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | Tmax: Time to Reach Maximum Plasma Concentration of Lemborexant and Its Metabolites M4, M9, M10 | M10 | 3.00 hours |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | Tmax: Time to Reach Maximum Plasma Concentration of Lemborexant and Its Metabolites M4, M9, M10 | Lemborexant | 1.00 hours |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | Tmax: Time to Reach Maximum Plasma Concentration of Lemborexant and Its Metabolites M4, M9, M10 | M9 | 1.25 hours |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | Tmax: Time to Reach Maximum Plasma Concentration of Lemborexant and Its Metabolites M4, M9, M10 | M4 | 1.75 hours |
| Cohort C: Healthy Participants (Control) | Tmax: Time to Reach Maximum Plasma Concentration of Lemborexant and Its Metabolites M4, M9, M10 | M10 | 4.00 hours |
| Cohort C: Healthy Participants (Control) | Tmax: Time to Reach Maximum Plasma Concentration of Lemborexant and Its Metabolites M4, M9, M10 | M4 | 2.00 hours |
| Cohort C: Healthy Participants (Control) | Tmax: Time to Reach Maximum Plasma Concentration of Lemborexant and Its Metabolites M4, M9, M10 | M9 | 1.50 hours |
| Cohort C: Healthy Participants (Control) | Tmax: Time to Reach Maximum Plasma Concentration of Lemborexant and Its Metabolites M4, M9, M10 | Lemborexant | 1.25 hours |
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.
Time frame: Day 1: Predose, 0.5 up to 312 hours postdose
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Mild Hepatic Impairment (Child Pugh Class A) | Vz/F: Apparent Volume of Distribution of Lemborexant | 1880 Liter (L) | Geometric Coefficient of Variation 72.7 |
| Cohort B: Moderate Hepatic Impairment (Child Pugh Class B) | Vz/F: Apparent Volume of Distribution of Lemborexant | 2170 Liter (L) | Geometric Coefficient of Variation 13.5 |
| Cohort C: Healthy Participants (Control) | Vz/F: Apparent Volume of Distribution of Lemborexant | 2130 Liter (L) | Geometric Coefficient of Variation 30.1 |