Study to Evaluate the Pharmacokinetics of Lemborexant (E2006) and Its Metabolites in Subjects With Normal Renal Function or With Severe Renal Impairment

An Open-label, Parallel-Group Study to Evaluate the Pharmacokinetics of Lemborexant and Its Metabolites in Subjects With Normal Renal Function or With Severe Renal Impairment

This study will be conducted to assess the effect of severe renal impairment on the pharmacokinetics of lemborexant after a single-dose administration.

Study Overview

• Status: Completed
• Conditions: Renal Impairment
• Intervention / Treatment: Drug: Lemborexant

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33014
      • Clinical Pharmacology of Miami, LLC
    • Orlando, Florida, United States, 32809
      • Orlando Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Inclusion Criteria for All Participants:

• Male or female participants, ages 18 to 79 years, inclusive, at the time of informed consent.
• Body Mass Index between 18 and 40 kilograms per meters squared (kg/m^2), 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.
• Participants with normal liver function.

Additional Inclusion Criteria for Healthy Participants:

• Estimated glomerular filtration rate (eGFR) is ≥ 90 mL/min/1.73 m^2, as determined by the Modification of Diet in Renal Disease (MDRD) formula.

Additional Inclusion Criteria for Participants with Renal Impairment:

- Diagnosis of severe renal impairment (eGFR is 15 to 29 mL/min/1.73 m^2, as determined by the MDRD formula) that has been stable (without any change in disease status) for 60 days prior to study Screening and is confirmed on Day -1, as determined by the investigator by MDRD formula. If the renal function classification for the participant changed from screening to Day -1, eGFR should be repeated once within 24 to 48 hours. If eGFR variability across these scheduled and repeat time points indicates the participant does not consistently meet the criteria for one renal category group, participant enrollment into a renal category group will be at the discretion of the medical monitor and investigator, in consultation with the Sponsor.

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.
• Intake of food supplements (including herbal preparations), foods or beverages that may affect cytochrome P450 (CYP) 3A4 (CYP3A4) 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 2 weeks before dosing until study discharge.
• Use of an herbal preparation containing Saint John's Wort within 4 weeks before dosing until study discharge.
• Known to be positive for human immunodeficiency virus.
• Presence of acute and active liver disease, or acute liver injury, as indicated by (1) an abnormal liver function test, or (2) clinical or laboratory signs of acute, active viral hepatitis (including B and C as demonstrated by positive serology at Screening). Participants with stable, chronic, inactive viral hepatitis B or C may be enrolled based on investigator's opinion.
• Corrected QT interval for heart rate on electrocardiograms (ECGs) by Fridericia's formula (QTcF) >480 milliseconds (msec) at Screening or Day -1. Before excluding a participant with QTcF >480 msec at Screening, ECG should be repeated once to confirm.
• A known or suspected history of drug or alcohol abuse disorder within 6 months prior to Screening.
• A positive urine drug test or a positive breathalyzer alcohol test at Screening or Day -1.
• Participation in another interventional clinical trial within 4 weeks, or 5 times the half-life of the investigational drug (whichever is longer), of lemborexant administration.
• Engaged in heavy/strenuous physical exercise within 2 weeks prior to check-in on Day -1 (e.g., marathon runners, weight lifters).
• Unwilling to abide by the study requirements, or in the opinion of the investigator, is not likely to complete the study.
• History of clinically significant drug or food allergies, or is presently experiencing significant seasonal allergies.
• Recent weight change that is considered clinically significant by the Investigator.
• Clinically significant findings revealed by physical examination, assessment of vital signs, ECG, or clinical laboratory testing.
• Use of any prohibited prescription or over-the-counter medication within 2 weeks or 5 half-lives (whichever is longer) before Screening, or plans to use any such treatment during the study. For participants with renal impairment, chronic stable administration of medications necessary for maintaining the clinical status of the participant may be permitted after consultation with the Medical Monitor.

Additional Exclusion Criteria for Healthy Participants:

• Presence of clinically significant illness requiring treatment or that may influence the outcome of the study (e.g., psychiatric disorders, disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, or cardiovascular system), a history of myocardial infraction, or a congenital abnormality.
• Receipt or donation of blood or blood products within 4 to 8 weeks prior to study drug administration.

Additional Exclusion Criteria for Participants With Renal Impairment:

• Any history of renal transplant.
• Any known significant bleeding diathesis (e.g., history of recent bleeding from esophageal varices), which could preclude multiple venipuncture or deep intramuscular injections.
• New significant illness that onset within 2 weeks prior to study drug administration.
• Current clinically relevant disease other than the renal impairment (e.g., cardiac, hepatic, gastrointestinal disorder, or a condition which may impact drug absorption), as determined by the investigator. Participants with a history of Type I or Type II diabetes may be eligible, providing that, in the investigator's opinion, the disease has been stable. Participants receiving insulin therapy may be eligible provided they have been on a stable (i.e., dose has not changed) treatment for at least 2 weeks prior to study enrollment and will continue the treatment throughout the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1: Severe Renal Impairment; Participants with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 milliliters per minute (mL/min/1.73 square meter [m^2]) and not on dialysis) will receive a single dose of 10 milligrams (mg) lemborexant (oral tablet) in the morning after an overnight fast.	Drug: Lemborexant; oral tablet; Other Names: E2006
Experimental: Group 2: Normal Renal Function; Participants with normal renal function (eGFR ≥90 mL/min/1.73 m^2) demographically matched to participants in Group 1 will receive a single dose of 10 mg lemborexant (oral tablet) in the morning after an overnight fast.	Drug: Lemborexant; oral tablet; Other Names: E2006

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum Observed Plasma Concentration (Cmax) of Lemborexant	Day 1: predose, 0.5 up to 240 hours postdose
Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours Post Dose (AUC[0-72h]) of Lemborexant	Day 1: predose, 0.5 up to 72 hours postdose
Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-t]) of Lemborexant	Day 1: predose, 0.5 up to 240 hours postdose
Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUC[0-inf]) of Lemborexant	Day 1: predose, 0.5 up to 240 hours postdose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax) of Metabolites of Lemborexant (M4, M9, and M10)		Day 1: predose, 0.5 up to 240 hours postdose
Time to Reach Maximum Plasma Concentration (Tmax) of Lemborexant and Its Metabolites (M4, M9, and M10)		Day 1: predose, 0.5 up to 240 hours postdose
Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours Post Dose (AUC[0-8h]) of Lemborexant and Its Metabolites (M4, M9, and M10)		Day 1: predose, 0.5 up to 8 hours postdose
Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours Post Dose (AUC[0-72h]) of Metabolites of Lemborexant (M4, M9, and M10)		Day 1: predose, 0.5 up to 72 hours postdose
Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-t]) of Metabolites of Lemborexant (M4, M9, and M10)		Day 1: predose, 0.5 up to 240 hours postdose
Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUC[0-inf]) of Metabolites of Lemborexant (M4, M9, and M10)		Day 1: predose, 0.5 up to 240 hours postdose
Area Under the Plasma Concentration-Time Curve Adjusted by Unbound Fraction of Plasma (AUCu) of Lemborexant and Its Metabolites (M4, M9, and M10)	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).	Day 1: predose, 0.5 up to 240 hours postdose
Percentage of AUC(0-inf) Based on Extrapolation (AUCex) of Lemborexant and Its Metabolites (M4, M9, and M10)	AUCex was calculated by dividing the difference of (AUC(0-inf) and AUC(0-t)) by value of AUC(0-inf) and then multiplying the value by 100.	Day 1: predose, 0.5 up to 240 hours postdose
Observed Terminal Elimination Half-life (t1/2) of Lemborexant and Its Metabolites (M4, M9, and 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.	Day 1: predose, 0.5 up to 240 hours postdose
Observed Elimination Rate Constant (LambdaZ) of Lemborexant and Its Metabolites (M4, M9, and M10)	Estimated by linear regression through at least three data points (not including tmax) in the terminal phase of the log concentration-time profile.	Day 1: predose, 0.5 up to 240 hours postdose
Apparent Body Clearance (CL/F) of Lemborexant	CL/F is the clearance for parent Lemborexant only and was calculated as Dose/[AUC0-inf]. Blood samples were analyzed for the amount of Lemborexant in the plasma.	Day 1: predose, 0.5 up to 240 hours postdose
Apparent Volume of Distribution (Vz/F) Based on the Terminal Phase of Lemborexant	The apparent volume of distribution gives information about the amount of Lemborexant distributed in body tissue rather than the blood/plasma. Vz/F for parent Lemborexant only was calculated as Dose /([ λz]*[AUC0-inf]).	Day 1: predose, 0.5 up to 240 hours postdose
Metabolite-to-Parent Ratio of AUC(0-inf), Corrected for Molecular Weights (MPR AUC[0-inf]) of Metabolites of Lemborexant (M4, M9, and M10)	The AUC metabolite to parent ratio (MPR) is the ratio of AUC(0-inf) of the individual metabolite to AUC(0-inf) of lemborexant, corrected for molecular weights.	Day 1: predose, 0.5 up to 240 hours postdose
Plasma Protein Unbound Fraction (Fu) of Lemborexant and Its Metabolites (M4, M9, and M10)	Unbound fraction of drug in plasma was calculated as 100% minus (-) mean percent of Lemborexant and Its Metabolites M4. M9. M10 bound to plasma protein for each participant.	Day 1: predose, 0.5 up to 240 hours postdose
Apparent Clearance Relative to the Unbound Plasma Concentration (CLu/F) 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.	Day 1: predose, 0.5 up to 240 hours postdose
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)		Up to Day 11
Number of Participants With Clinically Significant Laboratory Abnormalities		Up to Day 11
Number of Participants With Clinically Significant Abnormal Vital Sign Values		Up to Day 11
Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Parameter Values		Up to Day 11

Collaborators and Investigators

• Sponsor: Eisai Inc.
• Collaborators: Purdue Pharma LP

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2018
• Primary Completion (Actual): August 24, 2018
• Study Completion (Actual): August 24, 2018

Study Registration Dates

• First Submitted: February 16, 2018
• First Submitted That Met QC Criteria: February 16, 2018
• First Posted (Actual): February 22, 2018

Study Record Updates

• Last Update Posted (Actual): March 12, 2020
• Last Update Submitted That Met QC Criteria: March 3, 2020
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: pharmacokinetics; metabolites; normal renal function; E2006; healthy participants; severe renal impairment; lemborexant
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Hypnotics and Sedatives; Sleep Aids, Pharmaceutical; Orexin Receptor Antagonists; Lemborexant
• Other Study ID Numbers: E2006-A001-105

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No