Clinical trial NCT03443063: Study to Evaluate the Pharmacokinetics of Lemborexant (E2006) and Its Metabolites in Subjects With Normal Renal Function or With Severe Renal Impairment
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Impairment
Keywords: severe renal impairment
lemborexant
normal renal function
healthy participants
metabolites
E2006
pharmacokinetics
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
Collaborators: name: Purdue Pharma LP
First posted: 2018-02-22
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility criteria: 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.

Primary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of Lemborexant
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 72 Hours Post Dose (AUC[0-72h]) of Lemborexant
timeFrame: Day 1: predose, 0.5 up to 72 hours postdose
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-t]) of Lemborexant
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUC[0-inf]) of Lemborexant
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of Metabolites of Lemborexant (M4, M9, and M10)
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Lemborexant and Its Metabolites (M4, M9, and M10)
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: 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)
timeFrame: Day 1: predose, 0.5 up to 8 hours postdose
measure: 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)
timeFrame: Day 1: predose, 0.5 up to 72 hours postdose
measure: 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)
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUC[0-inf]) of Metabolites of Lemborexant (M4, M9, and M10)
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: Area Under the Plasma Concentration-Time Curve Adjusted by Unbound Fraction of Plasma (AUCu) of Lemborexant and Its Metabolites (M4, M9, and M10)
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: Percentage of AUC(0-inf) Based on Extrapolation (AUCex) of Lemborexant and Its Metabolites (M4, M9, and M10)
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: Observed Terminal Elimination Half-life (t1/2) of Lemborexant and Its Metabolites (M4, M9, and M10)
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: Observed Elimination Rate Constant (LambdaZ) of Lemborexant and Its Metabolites (M4, M9, and M10)
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: Apparent Body Clearance (CL/F) of Lemborexant
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: Apparent Volume of Distribution (Vz/F) Based on the Terminal Phase of Lemborexant
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: Metabolite-to-Parent Ratio of AUC(0-inf), Corrected for Molecular Weights (MPR AUC[0-inf]) of Metabolites of Lemborexant (M4, M9, and M10)
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: Plasma Protein Unbound Fraction (Fu) of Lemborexant and Its Metabolites (M4, M9, and M10)
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: Apparent Clearance Relative to the Unbound Plasma Concentration (CLu/F) Based on AUCu of Lemborexant
timeFrame: Day 1: predose, 0.5 up to 240 hours postdose
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Day 11
measure: Number of Participants With Clinically Significant Laboratory Abnormalities
timeFrame: Up to Day 11
measure: Number of Participants With Clinically Significant Abnormal Vital Sign Values
timeFrame: Up to Day 11
measure: Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Parameter Values
timeFrame: Up to Day 11
Other outcomes:
Locations:
city: Miami
country: United States
facility: Clinical Pharmacology of Miami, LLC
state: Florida
city: Orlando
country: United States
facility: Orlando Clinical Research Center
state: Florida
Study officials:
References: