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

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ClinicalTrials.gov Identifier: NCT03443063
Recruitment Status : Completed
First Posted : February 22, 2018
Last Update Posted : September 6, 2018
Sponsor:
Collaborator:
Purdue Pharma LP
Information provided by (Responsible Party):
Eisai Inc.

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.

Condition or disease Intervention/treatment Phase
Renal Impairment Drug: Lemborexant Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 29, 2018
Actual Primary Completion Date : August 24, 2018
Actual Study Completion Date : August 24, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Tests

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 Name: 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 Name: E2006




Primary Outcome Measures :
  1. Mean maximum plasma drug concentration (Cmax) of lemborexant [ Time Frame: Blood samples for lemborexant assessment will be obtained at predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 (Day 1); 24 and 36 (Day 2); 48 (Day 3); 72 (Day 4); 96 (Day 5); 120 (Day 6); 144 (Day 7); 168 (Day 8); and 240 (Day 11) hours postdose. ]
  2. Mean area under plasma concentration versus time curve from time = 0 to time of last quantifiable concentration (AUC[0-t]) of lemborexant [ Time Frame: Blood samples for lemborexant assessment will be obtained at predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 (Day 1); 24 and 36 (Day 2); 48 (Day 3); 72 (Day 4); 96 (Day 5); 120 (Day 6); 144 (Day 7); 168 (Day 8); and 240 (Day 11) hours postdose. ]
  3. Mean area under plasma concentration versus time curve from time = 0 to infinity (AUC[0-inf]) of lemborexant [ Time Frame: Blood samples for lemborexant assessment will be obtained at predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 (Day 1); 24 and 36 (Day 2); 48 (Day 3); 72 (Day 4); 96 (Day 5); 120 (Day 6); 144 (Day 7); 168 (Day 8); and 240 (Day 11) hours postdose. ]

Secondary Outcome Measures :
  1. Mean time to reach maximum plasma concentration (Tmax) of lemborexant and its metabolites [ Time Frame: Blood samples for lemborexant and metabolite assessment will be obtained at predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 (Day 1); 24 and 36 (Day 2); 48 (Day 3); 72 (Day 4); 96 (Day 5); 120 (Day 6); 144 (Day 7); 168 (Day 8); and 240 (Day 11) hours postdose ]
  2. Mean terminal phase plasma half-life (t½) of lemborexant and its metabolites [ Time Frame: Blood samples for lemborexant and metabolite assessment will be obtained at predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 (Day 1); 24 and 36 (Day 2); 48 (Day 3); 72 (Day 4); 96 (Day 5); 120 (Day 6); 144 (Day 7); 168 (Day 8); and 240 (Day 11) hours postdose ]
  3. Mean apparent total body clearance (CL/F) of lemborexant [ Time Frame: Blood samples for lemborexant assessment will be obtained at predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 (Day 1); 24 and 36 (Day 2); 48 (Day 3); 72 (Day 4); 96 (Day 5); 120 (Day 6); 144 (Day 7); 168 (Day 8); and 240 (Day 11) hours postdose. ]
  4. Mean apparent volume of distribution (Vz/F) of lemborexant [ Time Frame: Blood samples for lemborexant assessment will be obtained at predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 (Day 1); 24 and 36 (Day 2); 48 (Day 3); 72 (Day 4); 96 (Day 5); 120 (Day 6); 144 (Day 7); 168 (Day 8); and 240 (Day 11) hours postdose. ]
  5. AUC Metabolite Ratio [ Time Frame: Blood samples for lemborexant and metabolite assessment will be obtained at predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 (Day 1); 24 and 36 (Day 2); 48 (Day 3); 72 (Day 4); 96 (Day 5); 120 (Day 6); 144 (Day 7); 168 (Day 8); and 240 (Day 11) hours postdose ]
    The AUC metabolite ratio is the ratio of AUC(0-inf) of the individual metabolite to AUC(0-inf) of lemborexant, corrected for molecular weights.

  6. Plasma protein unbound fraction (fu) of lemborexant and its metabolites [ Time Frame: Blood samples for lemborexant and metabolite assessment will be obtained at 1 and 24 hours postdose. ]
  7. Mean AUC(0-inf) values adjusted by unbound fraction in plasma (AUCu) of lemborexant [ Time Frame: Blood samples for lemborexant assessment will be obtained at predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 (Day 1); 24 and 36 (Day 2); 48 (Day 3); 72 (Day 4); 96 (Day 5); 120 (Day 6); 144 (Day 7); 168 (Day 8); and 240 (Day 11) hours postdose. ]
  8. Mean apparent clearance relative to the unbound plasma concentration based on AUCu (CLu/F) of lemborexant [ Time Frame: Blood samples for lemborexant assessment will be obtained at predose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 (Day 1); 24 and 36 (Day 2); 48 (Day 3); 72 (Day 4); 96 (Day 5); 120 (Day 6); 144 (Day 7); 168 (Day 8); and 240 (Day 11) hours postdose. ]


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Ages Eligible for Study:   18 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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. Note: All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03443063


Locations
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United States, Florida
Clinical Pharmacology of Miami, LLC
Miami, Florida, United States, 33014
Orlando Clinical Research Center
Orlando, Florida, United States, 32809
Sponsors and Collaborators
Eisai Inc.
Purdue Pharma LP

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Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT03443063     History of Changes
Other Study ID Numbers: E2006-A001-105
First Posted: February 22, 2018    Key Record Dates
Last Update Posted: September 6, 2018
Last Verified: July 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Eisai Inc.:
severe renal impairment
lemborexant
normal renal function
healthy participants
metabolites
E2006
pharmacokinetics

Additional relevant MeSH terms:
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Renal Insufficiency
Kidney Diseases
Urologic Diseases