Alzheimer's Disease, Amnestic Mild Cognitive Impairment, Prodromal Alzheimer's Disease
Conditions
Brief summary
This study consists of Part I and an optional Part II. The purpose of Part I is to compare the plasma pharmacokinetics of verubecestat (MK-8931) following administration of a single oral dose of 40 mg MK-8931 to participants with moderate hepatic insufficiency (HI) to that of healthy matched controls. An interim safety and pharmacokinetic analysis on the basis of Part I will be performed in order to support the decision to continue with the optional Part II. If a decision to continue with Part II is made, participants with mild HI will be enrolled to receive a single oral dose of 40mg MK-8931. If any healthy participants from Part I do not meet the matching criteria for Part II additional healthy participants will be enrolled.
Interventions
DRUGMK-8931
MK-8931 40 mg
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
45 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
Participants with HI 1. Adult male or female participants, 45-85 years of age, inclusive, at screening. 2. Body Mass Index (BMI) ≥ 19 and ≤ 40 kg/m\^2, at screening. 3. Continuous non-smokers or light smokers (\< 10 cigarettes/day or the equivalent). 4. Baseline health is judged to be stable based on medical history (except for the hepatic insufficiency condition). 5. Participant has a diagnosis of chronic (\> 6 months), stable (no acute episodes of illness within the previous 2 months due to deterioration in hepatic function) HI with features of cirrhosis due to any etiology. 6. Part 1 only: Participant's score on the Child-Pugh scale must range from 7 to 9 (moderate HI) at screening. 7. Part 2 only: Participant's score on the Child-Pugh scale must range from 5 to 6 (mild HI) at screening. 8. Participants must be completely informed of the unknown risks of pregnancy and agree not to become pregnant or father a child during the time they are participating in this study. 9. For a female of childbearing potential: either be sexually inactive (abstinent) for 14 days prior to dosing and throughout the study or be using an acceptable birth control method. 10. Females of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first dose: * hysteroscopic sterilization; * bilateral tubal ligation or bilateral salpingectomy; * hysterectomy; * bilateral oophorectomy; or be postmenopausal with amenorrhea for at least 1 year prior to dosing and have follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status as per Investigator or designee's judgment. 11. Non-vasectomized male participants must agree to use a condom with spermicide or abstain from sexual intercourse from dosing until 90 days after dosing. 12. Male participants must agree not to donate sperm from dosing until 90 days after dosing. 13. Understands the study procedures in informed consent forms (ICFs), be willing and able to comply with the protocol, and provides written informed consent for the trial, including for Future Biomedical Research. Future Biomedical Research participation is voluntary and is not required in order to participate in the trial. Inclusion Criteria: Healthy Control Participants 1. Healthy adult male or female participants, 45-85 years of age, inclusive, at screening. 2. BMI ≥ 19 and ≤ 40 kg/m\^2 at screening. 3. Continuous non-smokers or light smokers (\< 10 cigarettes/day or the equivalent). 4. Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs, or electrocardiograms (ECGs), as deemed by the Investigator. 5. Participants must be completely informed of the unknown risks of pregnancy and agree not to become pregnant or father a child during the time they are participating in this study. 6. For a female of childbearing potential: either be sexually inactive (abstinent) for 14 days prior to dosing and throughout the study or be using an acceptable birth control method. 7. Females of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first dose: * hysteroscopic sterilization; * bilateral tubal ligation or bilateral salpingectomy; * hysterectomy; * bilateral oophorectomy; or be postmenopausal with amenorrhea for at least 1 year prior to dosing and have FSH serum levels consistent with postmenopausal status as per Investigator or designee's judgment. 8. Non-vasectomized male participants must agree to use a condom with spermicide or abstain from sexual intercourse from dosing until 90 days after dosing. 9. Male participants must agree not to donate sperm from dosing until 90 days after dosing. 10. Understands the study procedures in ICFs, be willing and able to comply with the protocol, and provides written informed consent for the trial, including for Future Biomedical Research. Future Biomedical Research participation is voluntary and is not required in order to participate in the trial.
Exclusion criteria
Participants with HI 1. Participant is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study. 2. History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the Investigator. 3. History of any illness that, in the opinion of the Investigator, might confound the results of the study or poses an additional risk to the participant by their participation in the study. 4. History or presence of alcoholism or drug abuse within the past 2 years prior to dosing. 5. History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related compounds. 6. Female participants who are pregnant or lactating. 7. Positive results for the urine drug and/or alcohol screen at screening or check-in, unless the positive drug screen is due to prescription drug use and is approved by the Investigator and the Sponsor Medical Monitor. 8. Positive results at screening for human immunodeficiency virus (HIV) or hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV; i.e., HCV antibody positive, HCV ribonucleic acid (RNA) positive) with decompensated liver disease. 9. Seated blood pressure is less than 90/40 mmHg or greater than 180/105 mmHg at screening. 10. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening. 11. Fridericia's correction of the QT interval (QTcF) is \> 480 msec or has ECG findings deemed abnormal with clinical significance by the Investigator or designee at screening. 12. Abnormal hemoglobin level deemed clinically significant by the Investigator at screening. 13. Unable to refrain from or anticipates the use of any medication or substance (including prescription or over-the-counter, vitamin supplements, natural or herbal supplements). 14. Has been on a diet incompatible with the Clinical Research Unit (CRU) -provided standard meals/snacks, in the opinion of the Investigator, within the 28 days prior to dosing of study drug, and throughout the study. 15. Donation of blood or had significant blood loss within 56 days prior to dosing of study drug. 16. Plasma donation within 28 days prior to dosing of study drug. 17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this study. 18. Participation in another clinical trial within 28 days prior to dosing. 19. Participant who dosed in one part (e.g., Part 1) will not be enrolled in the other part (e.g., Part 2).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Volume of Distribution of MK-8931 During the Terminal Phase After Extravascular Administration (Vz/F) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose | Geometric mean apparent volume of distribution of MK-8931 during the terminal phase after extravascular administration (Vz/F) was assessed. Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine Vz/F, defined as the total amount of MK-8931 administered normalized to the bioavailability of MK-8931 in the plasma during the terminal phase following oral MK-8931 administration. |
| Time to Maximum Observed MK-8931 Plasma Drug Concentration (Tmax) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after MK-8931 40 mg dose | Median time to maximum observed MK-8931 plasma drug concentration (Tmax) was assessed. Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine Tmax, defined as the amount of time required following MK-8931 administration for the plasma concentration of MK-8931 to reach maximum observed concentration. |
| Apparent Terminal Half-Life of MK-8931 (t1/2) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose | Geometric mean apparent terminal half-life (t1/2) of MK-8931 was assessed. Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine t1/2, defined as the time required for the plasma MK-8931 concentration to decrease to 50% of maximum. |
| Area Under the Concentration Versus Time Curve of MK-8931 From 0 to Infinity (AUC0-∞) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose | Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine AUC0-∞, defined as the area under the MK-8931 concentration versus time curve from 0 (predose) extrapolated to infinity after a single oral dose of MK-8931 40 mg. Individual AUC0-∞ values were natural log (ln) transformed and evaluated with an analysis of covariance (ANCOVA) model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for AUC0-∞ in each arm. |
| Maximum Observed Plasma Concentration of MK-8931 (Cmax) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after MK-8931 40 mg dose | Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine Cmax, defined as the maximum plasma concentration of MK-8931 observed following oral dosing. Individual Cmax values were ln-transformed and evaluated with an ANCOVA model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for Cmax in each arm. |
| Area Under the Concentration Versus Time Curve of MK-8931 From 0 to the Time of the Last Quantifiable (Above LLOQ) Sample (AUC0-last) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose | Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine AUC0-last, defined as the area under the MK-8931 concentration versus time curve from 0 (predose) to the time of the last sample with quantifiable MK-8931 (above the lower limit of quantification; LLOQ) after a single oral dose of MK-8931 40 mg. Individual AUC0-last values were ln-transformed and evaluated with an ANCOVA model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for AUC0-last in each arm. |
| Area Under the Concentration Versus Time Curve of MK-8931 From 0 to 24 Hours (AUC0-24hr) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours after MK-8931 40 mg dose | Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine AUC0-24hr, defined as the area under the MK-8931 concentration versus time curve from 0 (predose) until 24 hours after single oral dosing of MK-8931 40 mg. Individual AUC0-24hr values were ln-transformed and evaluated with an ANCOVA model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for AUC0-24hr in each arm. |
| Plasma Concentration of MK-8931 at 24 Hours (C24hr) | 24 hours after MK-8931 40 mg dose | Blood samples were collected 24 hours following oral dosing of MK-8931 and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified to determine C24hr, defined as the plasma concentration of MK-8931 at 24 hours after single oral dosing of MK-8931 40 mg. Individual C24hr values were ln-transformed and evaluated with an ANCOVA model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for C24hr in each arm. |
| Apparent Clearance of MK-8931 After Extravascular Administration (CL/F) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose | Geometric mean apparent clearance of MK-8931 after extravascular administration (CL/F) was assessed. Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine CL/F, defined as the rate of MK-8931 elimination normalized to the bioavailability of MK-8931 in the plasma following oral MK-8931 administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Discontinuing Study Due to an Adverse Event | Up to 14 days following MK-8931 40 mg administration. | The number of participants discontinuing study due to an AE was assessed. An AE is any unfavorable and unintended medical occurrence, symptom, or disease witnessed in a participant, regardless of whether or not a causal relationship with the study treatment can be demonstrated. Further, any worsening of a preexisting condition that is temporally associated with the use of the study treatment is also considered an AE. |
| Number of Participants Experiencing an Adverse Event | Up to 14 days following MK-8931 40 mg administration. | The number of participants experiencing an adverse event (AE) was assessed. An AE is any unfavorable and unintended medical occurrence, symptom, or disease witnessed in a participant, regardless of whether or not a causal relationship with the study treatment can be demonstrated. Further, any worsening of a preexisting condition that is temporally associated with the use of the study treatment is also considered an AE. |
Participant flow
Pre-assignment details
Per protocol, this study was divided into Part I and an optional Part II, with Part II initiating only after interim analysis (IA) of Part I. Following Part I IA, the pharmacokinetic (PK) criterion necessary to initiate enrollment for Part II was not met. As a result, the study was completed normally without enrollment into the optional Part II.
Participants by arm
| Arm | Count |
|---|---|
| Part I: MK-8931 40 mg in Moderate HI Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate HI in fasted state (Part I) | 8 |
| Part I: MK-8931 40 mg in Healthy Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I) | 8 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part I: MK-8931 40 mg in Moderate HI Participants | Part I: MK-8931 40 mg in Healthy Participants | Total |
|---|---|---|---|
| Age, Continuous | 61.0 years STANDARD_DEVIATION 6.1 | 61.4 years STANDARD_DEVIATION 4.8 | 61.2 years STANDARD_DEVIATION 5.3 |
| Body Mass Index (BMI) | 29.688 kg/m^2 | 30.313 kg/m^2 | 30.000 kg/m^2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 1 / 8 | 0 / 8 |
Outcome results
Primary
Apparent Clearance of MK-8931 After Extravascular Administration (CL/F)
Geometric mean apparent clearance of MK-8931 after extravascular administration (CL/F) was assessed. Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine CL/F, defined as the rate of MK-8931 elimination normalized to the bioavailability of MK-8931 in the plasma following oral MK-8931 administration.
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose
Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of CL/F. One participant with moderate HI discontinued study prior to collection of samples at 72, 96, and 120 hours post-dose and was excluded from analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part I: MK-8931 40 mg in Moderate HI Participants | Apparent Clearance of MK-8931 After Extravascular Administration (CL/F) | 28.4 Liters/hr | Geometric Coefficient of Variation 26.3 |
| Part I: MK-8931 40 mg in Healthy Participants | Apparent Clearance of MK-8931 After Extravascular Administration (CL/F) | 29.0 Liters/hr | Geometric Coefficient of Variation 22.7 |
Primary
Apparent Terminal Half-Life of MK-8931 (t1/2)
Geometric mean apparent terminal half-life (t1/2) of MK-8931 was assessed. Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine t1/2, defined as the time required for the plasma MK-8931 concentration to decrease to 50% of maximum.
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose
Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of t1/2. One participant with moderate HI discontinued study prior to collection of samples at 72, 96, and 120 hours post-dose and was excluded from analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part I: MK-8931 40 mg in Moderate HI Participants | Apparent Terminal Half-Life of MK-8931 (t1/2) | 23.0 hr | Geometric Coefficient of Variation 15.7 |
| Part I: MK-8931 40 mg in Healthy Participants | Apparent Terminal Half-Life of MK-8931 (t1/2) | 24.7 hr | Geometric Coefficient of Variation 9.3 |
Primary
Apparent Volume of Distribution of MK-8931 During the Terminal Phase After Extravascular Administration (Vz/F)
Geometric mean apparent volume of distribution of MK-8931 during the terminal phase after extravascular administration (Vz/F) was assessed. Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine Vz/F, defined as the total amount of MK-8931 administered normalized to the bioavailability of MK-8931 in the plasma during the terminal phase following oral MK-8931 administration.
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose
Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of Vz/F. One participant with moderate HI discontinued study prior to collection of samples at 72, 96, and 120 hours post-dose and was excluded from analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part I: MK-8931 40 mg in Moderate HI Participants | Apparent Volume of Distribution of MK-8931 During the Terminal Phase After Extravascular Administration (Vz/F) | 940 Liters | Geometric Coefficient of Variation 27.3 |
| Part I: MK-8931 40 mg in Healthy Participants | Apparent Volume of Distribution of MK-8931 During the Terminal Phase After Extravascular Administration (Vz/F) | 1030 Liters | Geometric Coefficient of Variation 26.1 |
Primary
Area Under the Concentration Versus Time Curve of MK-8931 From 0 to 24 Hours (AUC0-24hr)
Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine AUC0-24hr, defined as the area under the MK-8931 concentration versus time curve from 0 (predose) until 24 hours after single oral dosing of MK-8931 40 mg. Individual AUC0-24hr values were ln-transformed and evaluated with an ANCOVA model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for AUC0-24hr in each arm.
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours after MK-8931 40 mg dose
Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of AUC0-24hr.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part I: MK-8931 40 mg in Moderate HI Participants | Area Under the Concentration Versus Time Curve of MK-8931 From 0 to 24 Hours (AUC0-24hr) | 1.90 µM*hr |
| Part I: MK-8931 40 mg in Healthy Participants | Area Under the Concentration Versus Time Curve of MK-8931 From 0 to 24 Hours (AUC0-24hr) | 1.88 µM*hr |
Comparison: Per study protocol, the purpose of this analysis is only to estimate the effect of moderate HI on AUC0-24hr; no hypothesis testing was planned for this outcome measure.90% CI: [0.8, 1.27]
Primary
Area Under the Concentration Versus Time Curve of MK-8931 From 0 to Infinity (AUC0-∞)
Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine AUC0-∞, defined as the area under the MK-8931 concentration versus time curve from 0 (predose) extrapolated to infinity after a single oral dose of MK-8931 40 mg. Individual AUC0-∞ values were natural log (ln) transformed and evaluated with an analysis of covariance (ANCOVA) model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for AUC0-∞ in each arm.
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose
Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of AUC0-∞. One participant with moderate HI discontinued study prior to collection of samples at 72, 96, and 120 hours post-dose and was excluded from analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part I: MK-8931 40 mg in Moderate HI Participants | Area Under the Concentration Versus Time Curve of MK-8931 From 0 to Infinity (AUC0-∞) | 3.48 micromolar(µM)*hour(hr) |
| Part I: MK-8931 40 mg in Healthy Participants | Area Under the Concentration Versus Time Curve of MK-8931 From 0 to Infinity (AUC0-∞) | 3.34 micromolar(µM)*hour(hr) |
Comparison: Per study protocol, the purpose of this analysis is only to estimate the effect of moderate HI on AUC0-∞; no hypothesis testing was planned for this outcome measure.90% CI: [0.83, 1.3]
Primary
Area Under the Concentration Versus Time Curve of MK-8931 From 0 to the Time of the Last Quantifiable (Above LLOQ) Sample (AUC0-last)
Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine AUC0-last, defined as the area under the MK-8931 concentration versus time curve from 0 (predose) to the time of the last sample with quantifiable MK-8931 (above the lower limit of quantification; LLOQ) after a single oral dose of MK-8931 40 mg. Individual AUC0-last values were ln-transformed and evaluated with an ANCOVA model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for AUC0-last in each arm.
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose
Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of AUC0-last. One participant with moderate HI discontinued study prior to collection of samples at 72, 96, and 120 hours post-dose and was excluded from analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part I: MK-8931 40 mg in Moderate HI Participants | Area Under the Concentration Versus Time Curve of MK-8931 From 0 to the Time of the Last Quantifiable (Above LLOQ) Sample (AUC0-last) | 3.35 µM*hr |
| Part I: MK-8931 40 mg in Healthy Participants | Area Under the Concentration Versus Time Curve of MK-8931 From 0 to the Time of the Last Quantifiable (Above LLOQ) Sample (AUC0-last) | 3.22 µM*hr |
Comparison: Per study protocol, the purpose of this analysis is only to estimate the effect of moderate HI on AUC0-last; no hypothesis testing was planned for this outcome measure.90% CI: [0.82, 1.31]
Primary
Maximum Observed Plasma Concentration of MK-8931 (Cmax)
Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine Cmax, defined as the maximum plasma concentration of MK-8931 observed following oral dosing. Individual Cmax values were ln-transformed and evaluated with an ANCOVA model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for Cmax in each arm.
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after MK-8931 40 mg dose
Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of Cmax.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part I: MK-8931 40 mg in Moderate HI Participants | Maximum Observed Plasma Concentration of MK-8931 (Cmax) | 154 nanomolar (nM) |
| Part I: MK-8931 40 mg in Healthy Participants | Maximum Observed Plasma Concentration of MK-8931 (Cmax) | 144 nanomolar (nM) |
Comparison: Per study protocol, the purpose of this analysis is only to estimate the effect of moderate HI on Cmax; no hypothesis testing was planned for this outcome measure.90% CI: [0.77, 1.5]
Primary
Plasma Concentration of MK-8931 at 24 Hours (C24hr)
Blood samples were collected 24 hours following oral dosing of MK-8931 and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified to determine C24hr, defined as the plasma concentration of MK-8931 at 24 hours after single oral dosing of MK-8931 40 mg. Individual C24hr values were ln-transformed and evaluated with an ANCOVA model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for C24hr in each arm.
Time frame: 24 hours after MK-8931 40 mg dose
Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of C24hr.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part I: MK-8931 40 mg in Moderate HI Participants | Plasma Concentration of MK-8931 at 24 Hours (C24hr) | 51.1 nM |
| Part I: MK-8931 40 mg in Healthy Participants | Plasma Concentration of MK-8931 at 24 Hours (C24hr) | 47.1 nM |
Comparison: Per study protocol, the purpose of this analysis is only to estimate the effect of moderate HI on C24hr; no hypothesis testing was planned for this outcome measure.90% CI: [0.9, 1.3]
Primary
Time to Maximum Observed MK-8931 Plasma Drug Concentration (Tmax)
Median time to maximum observed MK-8931 plasma drug concentration (Tmax) was assessed. Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine Tmax, defined as the amount of time required following MK-8931 administration for the plasma concentration of MK-8931 to reach maximum observed concentration.
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after MK-8931 40 mg dose
Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of Tmax.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part I: MK-8931 40 mg in Moderate HI Participants | Time to Maximum Observed MK-8931 Plasma Drug Concentration (Tmax) | 1.00 hr |
| Part I: MK-8931 40 mg in Healthy Participants | Time to Maximum Observed MK-8931 Plasma Drug Concentration (Tmax) | 2.00 hr |
Secondary
Number of Participants Discontinuing Study Due to an Adverse Event
The number of participants discontinuing study due to an AE was assessed. An AE is any unfavorable and unintended medical occurrence, symptom, or disease witnessed in a participant, regardless of whether or not a causal relationship with the study treatment can be demonstrated. Further, any worsening of a preexisting condition that is temporally associated with the use of the study treatment is also considered an AE.
Time frame: Up to 14 days following MK-8931 40 mg administration.
Population: All participants as treated, consisting of all participants receiving the single dose of MK-8931 40 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part I: MK-8931 40 mg in Moderate HI Participants | Number of Participants Discontinuing Study Due to an Adverse Event | 1 Participants |
| Part I: MK-8931 40 mg in Healthy Participants | Number of Participants Discontinuing Study Due to an Adverse Event | 0 Participants |
Secondary
Number of Participants Experiencing an Adverse Event
The number of participants experiencing an adverse event (AE) was assessed. An AE is any unfavorable and unintended medical occurrence, symptom, or disease witnessed in a participant, regardless of whether or not a causal relationship with the study treatment can be demonstrated. Further, any worsening of a preexisting condition that is temporally associated with the use of the study treatment is also considered an AE.
Time frame: Up to 14 days following MK-8931 40 mg administration.
Population: All participants as treated, consisting of all participants receiving the single dose of MK-8931 40 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part I: MK-8931 40 mg in Moderate HI Participants | Number of Participants Experiencing an Adverse Event | 1 Participants |
| Part I: MK-8931 40 mg in Healthy Participants | Number of Participants Experiencing an Adverse Event | 0 Participants |