Hepatic Insufficiency
Conditions
Brief summary
This open-label, non-randomized study was designed to compare pharmacokinetics of a single 50 milligram (mg) dose of MK-0822 in participants with and without moderate hepatic insufficiency (abnormal liver function) in order to determine to what degree hepatic dysfunction may impact therapeutic blood levels of MK-0822. The primary hypothesis is that plasma AUC0-∞ of odanacatib in participants with moderate hepatic insufficiency is similar to that in matched healthy participants following a single 50 mg oral dose.
Interventions
DRUGMK-0822
A single oral dose (50 mg tablet) of MK 0822 will be administered on Day 1 after an overnight fast.
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 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Not currently pregnant, nursing or planning to be pregnant through-out the course of the study; agree to use specified contraception per protocol requirement * Body Mass Index (BMI) of ≤ 39 kg/m\^2 (not obese) * Judged to be in good health (for healthy participant population) * Non-smoker for the past 6-months; social smokers (smoke less than 10 cigarettes within the past 3 months; or per discretion of the study Investigator, quit smoking within the past 3 months. * Diagnosed with chronic (more than 6 months), stable (no acute episodes of illness within the previous 2 months) hepatic insufficiency (liver dysfunction) with features of cirrhosis due to any cause (for the moderate hepatic insufficiency participant population) * Possess the ability to understand the study, grant voluntary informed consent and willingly comply with all study requirements
Exclusion criteria
* Does not meet the age requirement, is mentally or legally incapacitated, has or is expected to have significant emotional problems, or a history of a clinically significant psychiatric disorder * Has been diagnosed with a disease or medical condition which may pose a risk to the participant or may confound the study results * Compromised renal (kidney) function, significant organ system disease(s) or cancer(s) * Unable to refrain from or anticipates the use of any new medication, including prescription and non-prescription drugs or herbal remedies * Meets the requirements of the study in regard to current medication profile including: prescribed medications, caffeine, alcohol, over-the-counter drugs, herbals and nutritional products; with expected non-use of recreational (illicit) drugs associated with misuse, abuse and/or addiction * Had surgery, donated 1 unit of blood or received another investigational study medication within 4 weeks prior to the study's first dose of investigational product * History of multiple and/or severe allergies, or has had a life-threatening reaction or inability to tolerate prescription or non-prescription drugs or food
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of MK-0822 From Time 0 to Infinity (AUC0-∞) After Single Dose | Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose | For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of AUC0-∞ (Total AUC). AUC0-∞ is a measure of total drug exposure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Concentration (Tmax) of MK-0822 After Single Dose | Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose | For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of Tmax. |
| Maximum Concentration (Cmax) of MK-0822 After Single Dose | Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose | For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of Cmax. |
| Apparent Terminal Half-life (t1/2) of MK-0822 After Single Dose | Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose | Apparent terminal half-life is the time required to divide the plasma (serum) concentration by two after reaching pseudo-equilibrium. (Note: it is not the time required to eliminate half the administered dose.) For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of t1/2. Results are presented using harmonic mean and jackknife standard deviation. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Moderate Hepatic Insufficiency Group Single-dose administration of odanacatib 50 mg to participants with moderate hepatic insufficiency. | 8 |
| Healthy Matched Control Group Single-dose administration of odanacatib 50 mg to healthy matched control participants. | 9 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Moderate Hepatic Insufficiency Group | Healthy Matched Control Group | Total |
|---|---|---|---|
| Age, Continuous | 53.1 years STANDARD_DEVIATION 4.9 | 54.2 years STANDARD_DEVIATION 5.3 | 53.7 years STANDARD_DEVIATION 5 |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 8 | 1 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 9 |
Outcome results
Primary
Area Under the Concentration-time Curve of MK-0822 From Time 0 to Infinity (AUC0-∞) After Single Dose
For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of AUC0-∞ (Total AUC). AUC0-∞ is a measure of total drug exposure.
Time frame: Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose
Population: The per protocol population consisted of all participants who complied with the protocol sufficiently to ensure that results will likely exhibit the effects of treatment according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Moderate Hepatic Insufficiency Group | Area Under the Concentration-time Curve of MK-0822 From Time 0 to Infinity (AUC0-∞) After Single Dose | 28.84 μM*hr |
| Healthy Matched Control Group | Area Under the Concentration-time Curve of MK-0822 From Time 0 to Infinity (AUC0-∞) After Single Dose | 33.79 μM*hr |
Comparison: Natural log-transformed plasma values were analyzed using an analysis of covariance (ANCOVA) model with a categorical factor for population (moderate hepatic insufficiency participants, healthy matched control participants) and continuous covariates for age and body mass index (BMI). Data are back transformed to geometric least-squares mean ratio (GMR) (moderate hepatic insufficiency / healthy) and 90% confidence intervals.90% CI: [0.61, 1.19]
Secondary
Apparent Terminal Half-life (t1/2) of MK-0822 After Single Dose
Apparent terminal half-life is the time required to divide the plasma (serum) concentration by two after reaching pseudo-equilibrium. (Note: it is not the time required to eliminate half the administered dose.) For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of t1/2. Results are presented using harmonic mean and jackknife standard deviation.
Time frame: Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose
Population: The per protocol population consisted of all participants who complied with the protocol sufficiently to ensure that results will likely exhibit the effects of treatment according to the underlying scientific model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Insufficiency Group | Apparent Terminal Half-life (t1/2) of MK-0822 After Single Dose | 91.5 hr | Standard Deviation 30.1 |
| Healthy Matched Control Group | Apparent Terminal Half-life (t1/2) of MK-0822 After Single Dose | 70.5 hr | Standard Deviation 10.2 |
Secondary
Maximum Concentration (Cmax) of MK-0822 After Single Dose
For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of Cmax.
Time frame: Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose
Population: The per protocol population consisted of all participants who complied with the protocol sufficiently to ensure that results will likely exhibit the effects of treatment according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Moderate Hepatic Insufficiency Group | Maximum Concentration (Cmax) of MK-0822 After Single Dose | 199.41 nM |
| Healthy Matched Control Group | Maximum Concentration (Cmax) of MK-0822 After Single Dose | 279.59 nM |
Comparison: Natural log-transformed plasma values were analyzed using an ANCOVA model with a categorical factor for population (moderate hepatic insufficiency participants, healthy matched control participants) and continuous covariates for age and BMI. Data are back transformed to GMR (moderate hepatic insufficiency / healthy) and 90% confidence intervals.90% CI: [0.51, 1]
Secondary
Time to Maximum Concentration (Tmax) of MK-0822 After Single Dose
For healthy and moderate hepatic insufficiency participants, plasma samples were collected from predose to 336 hours postdose for determination of Tmax.
Time frame: Pre-dose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours postdose
Population: The per protocol population consisted of all participants who complied with the protocol sufficiently to ensure that results will likely exhibit the effects of treatment according to the underlying scientific model.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Moderate Hepatic Insufficiency Group | Time to Maximum Concentration (Tmax) of MK-0822 After Single Dose | 4.00 hr |
| Healthy Matched Control Group | Time to Maximum Concentration (Tmax) of MK-0822 After Single Dose | 24.00 hr |