Hepatic Insufficiency, Insomnia
Conditions
Keywords
Hepatic Insufficiency
Brief summary
This study will determine whether the plasma concentration-time profile and pharmacokinetics (PK) of suvorexant (MK-4305) in participants with moderate and mild hepatic insufficiency are similar to those observed in healthy participants.
Detailed description
Study Design: This study plans to enroll 16 participants in Part I (8 participants with moderate hepatic insufficiency and 8 healthy participants) and 16 participants in Part II (8 participants with mild hepatic insufficiency and 8 healthy participants). Part II will be conducted only if the primary hypothesis is not met and there is a significant difference in the PK of suvorexant between healthy participants and moderate hepatic insufficiency participants in Part I.
Interventions
DRUGSuvorexant
single 20 mg dose of suvorexant will be administered as 2 x 10 mg film coated tablets on Day 1 after an overnight fast with water.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
for Hepatic Insufficiency Participants: * Females of reproductive potential must have a negative pregnancy test and agree to use (and/or have their partner use) two acceptable methods of birth control * Body Mass Index (BMI) ≤35 kg/m\^2 prior to start of study * Diagnosis of stable hepatic insufficiency * Smoking is restricted to ≤10 cigarettes per day Inclusion Criteria for Healthy Matched Participants: * Females of reproductive potential must have a negative pregnancy test and agree to use (and/or have their partner use) two acceptable methods of birth control * BMI within approximately 20% of that of his/her hepatic participant * Participant is healthy * Participant is matched by race, gender, age (+/- 5 yrs) to his/her hepatic participant enrolled in the study * Smoking is restricted to ≤10 cigarettes per day
Exclusion criteria
for Hepatic Insufficiency Participants: * Participant is mentally or legally incapacitated * History of a clinically significant psychiatric disorder over the last 5 to 10 years * Participant has a history of any illness not related to his/her hepatic insufficiency * History of a persistent sleep abnormality occurring for at least three (3) months * Participant has a history of stroke, chronic seizures, or major neurological disorder * History of clinically significant hematological, immunological, renal, respiratory, or genitourinary abnormalities, uncomplicated kidney stones or childhood asthma * History of cancer * History of cataplexy * Participant is a nursing mother * Participant consumes \>3 servings of alcohol a day * Participant consumes \>6 caffeine servings a day * History of multiple and/or severe allergies * Participant is currently using or has history of illegal drug use * Participant has traveled across 3 or more time zones within 2 weeks of study participation * Participant works a night shift and is not able to avoid night shift work within 1 week before each treatment visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve (AUC) From Time Zero to Infinity (0-∞) After Single Dose Suvorexant: Moderate Hepatic Insufficiency Participants Versus Healthy Participants (Part I) | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, 96, 120, and 144 hours post-dose | Overall exposure was assessed by the area under the plasma concentration versus time curve from time zero to infinity (AUC\[0-∞\]). AUC(0-∞) was calculated as the sum of the AUC to the last time point with a detectable plasma concentration (AUC\[0-last\]) and Ct/λ, where Ct was the last measurable concentration and λ was the apparent terminal rate constant. |
| AUC(0-∞) After Single Dose Suvorexant: Mild Hepatic Insufficiency Participants Versus Healthy Participants (Part II) | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, 96, 120, and 144 hours post-dose | Overall exposure was assessed by the area under the plasma concentration versus time curve from time zero to infinity (AUC\[0-∞\]). AUC(0-∞) was calculated as the sum of the AUC to the last time point with a detectable plasma concentration (AUC\[0-last\]) and Ct/λ, where Ct was the last measurable concentration and λ was the apparent terminal rate constant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Suvorexant After Single Dose: Moderate Hepatic Insufficiency Participants Versus Healthy Participants | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, 96, 120, and 144 hours post-dose | Cmax was defined as the maximum observed concentration of a drug after administration. |
| Number of Participants With an Adverse Event (AE) | From administration of study drug through 14 days after administration of study drug | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. |
| Number of Participants Who Discontinued Study Due to an AE | From administration of study drug through 14 days after administration of study drug | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. |
Participant flow
Pre-assignment details
16 participants were enrolled in Part I of the study. Because the primary hypothesis was met, no participants were enrolled in Part II of the study.
Participants by arm
| Arm | Count |
|---|---|
| Participants With Moderate Hepatic Insufficiency (Part I) Participants with moderate hepatic insufficiency received a single dose of 20 mg open-label suvorexant. | 8 |
| Healthy Participants (Part I) Healthy participants matched to participants with moderate hepatic insufficiency received a single dose of 20 mg open-label suvorexant. | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | Participants With Moderate Hepatic Insufficiency (Part I) | Healthy Participants (Part I) | Total |
|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 5.1 | 57 years STANDARD_DEVIATION 4 | 57.3 years STANDARD_DEVIATION 4.5 |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 8 | 5 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve (AUC) From Time Zero to Infinity (0-∞) After Single Dose Suvorexant: Moderate Hepatic Insufficiency Participants Versus Healthy Participants (Part I)
Overall exposure was assessed by the area under the plasma concentration versus time curve from time zero to infinity (AUC\[0-∞\]). AUC(0-∞) was calculated as the sum of the AUC to the last time point with a detectable plasma concentration (AUC\[0-last\]) and Ct/λ, where Ct was the last measurable concentration and λ was the apparent terminal rate constant.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, 96, 120, and 144 hours post-dose
Population: All Treated Participants
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Participants With Moderate Hepatic Insufficiency (Part I) | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time Zero to Infinity (0-∞) After Single Dose Suvorexant: Moderate Hepatic Insufficiency Participants Versus Healthy Participants (Part I) | 14.09 μM•hr |
| Healthy Participants (Part I) | Area Under the Plasma Concentration Versus Time Curve (AUC) From Time Zero to Infinity (0-∞) After Single Dose Suvorexant: Moderate Hepatic Insufficiency Participants Versus Healthy Participants (Part I) | 13.73 μM•hr |
Comparison: The geometric mean (GM) for each participant group and the corresponding 95% confidence interval (CI) were calculated for AUC(0-∞) using an analysis of covariance (ANCOVA) model.~The AUC(0-∞) geometric mean ratio (GMR) of the 2 participant groups was used to test the primary hypothesis, which was that the AUC(0-∞) of suvorexant following a single 20-mg oral dose would be similar between participants with moderate hepatic insufficiency and healthy matched control participants.90% CI: [0.74, 1.43]ANCOVA
Primary
AUC(0-∞) After Single Dose Suvorexant: Mild Hepatic Insufficiency Participants Versus Healthy Participants (Part II)
Overall exposure was assessed by the area under the plasma concentration versus time curve from time zero to infinity (AUC\[0-∞\]). AUC(0-∞) was calculated as the sum of the AUC to the last time point with a detectable plasma concentration (AUC\[0-last\]) and Ct/λ, where Ct was the last measurable concentration and λ was the apparent terminal rate constant.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, 96, 120, and 144 hours post-dose
Population: Per protocol, the decision to perform AUC(0-∞) analysis in mild hepatic insufficiency participants was conditional on results of AUC(0-∞) analysis in moderate hepatic insufficiency participants. Since the primary hypothesis in moderate hepatic insufficiency participants was met, AUC(0-∞) analysis in mild hepatic insufficiency was not done.
Secondary
Maximum Plasma Concentration (Cmax) of Suvorexant After Single Dose: Moderate Hepatic Insufficiency Participants Versus Healthy Participants
Cmax was defined as the maximum observed concentration of a drug after administration.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, 96, 120, and 144 hours post-dose
Population: All Treated Participants
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Participants With Moderate Hepatic Insufficiency (Part I) | Maximum Plasma Concentration (Cmax) of Suvorexant After Single Dose: Moderate Hepatic Insufficiency Participants Versus Healthy Participants | 0.800 μM |
| Healthy Participants (Part I) | Maximum Plasma Concentration (Cmax) of Suvorexant After Single Dose: Moderate Hepatic Insufficiency Participants Versus Healthy Participants | 0.854 μM |
Comparison: The GM for each participant group and the corresponding 95% CI were calculated for Cmax using an ANCOVA model.~The Cmax GMR of the 2 participant groups was used to test the primary hypothesis, which was that the Cmax of suvorexant following a single 20-mg oral dose would be similar between participants with moderate hepatic insufficiency and healthy matched control participants.90% CI: [0.68, 1.29]ANCOVA
Secondary
Number of Participants Who Discontinued Study Due to an AE
An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug.
Time frame: From administration of study drug through 14 days after administration of study drug
Population: All Treated Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participants With Moderate Hepatic Insufficiency (Part I) | Number of Participants Who Discontinued Study Due to an AE | 0 participants |
| Healthy Participants (Part I) | Number of Participants Who Discontinued Study Due to an AE | 0 participants |
Secondary
Number of Participants With an Adverse Event (AE)
An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug.
Time frame: From administration of study drug through 14 days after administration of study drug
Population: All Treated Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participants With Moderate Hepatic Insufficiency (Part I) | Number of Participants With an Adverse Event (AE) | 7 participants |
| Healthy Participants (Part I) | Number of Participants With an Adverse Event (AE) | 5 participants |