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

Renal Impairment Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03443063
• Other study ID #: E2006-A001-105
• Status: Completed
• Phase: Phase 1
• Start date: February 7, 2018
• Est. completion date: August 24, 2018

Study information

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

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: August 24, 2018
• Est. primary completion date: August 24, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 79 Years

Eligibility

Inclusion Criteria:

Inclusion Criteria for All Participants:

• Male or female participants, ages 18 to 79 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.

Related Conditions & MeSH terms

• Renal Impairment
• Renal Insufficiency

Intervention

Drug:
• Lemborexant
oral tablet

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Eisai Inc.	Purdue Pharma LP

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Observed Plasma Concentration (Cmax) of Lemborexant		Day 1: predose, 0.5 up to 240 hours postdose
Primary	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
Primary	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
Primary	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	Maximum Observed Plasma Concentration (Cmax) of Metabolites of Lemborexant (M4, M9, and M10)		Day 1: predose, 0.5 up to 240 hours postdose
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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 /([ ?z]*[AUC0-inf]).	Day 1: predose, 0.5 up to 240 hours postdose
Secondary	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
Secondary	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
Secondary	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
Secondary	Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)		Up to Day 11
Secondary	Number of Participants With Clinically Significant Laboratory Abnormalities		Up to Day 11
Secondary	Number of Participants With Clinically Significant Abnormal Vital Sign Values		Up to Day 11
Secondary	Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Parameter Values		Up to Day 11