Moderate Hepatic Impairment
Conditions
Brief summary
The primary purpose of this study is to compare the plasma pharmacokinetics (PK) of belzutifan (MK-6482) following a single oral 80 mg dose of belzutifan in participants with moderate hepatic impairment to that of healthy matched control participants. This study will also evaluate the safety and tolerability of a single oral 80 mg dose of belzutifan in participants with moderate hepatic impairment.
Interventions
DRUGBelzutifan
Two 40 mg tablets given as a single oral 80 mg dose.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Parallel Group
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
All Participants: * Is in good health. * Has a body mass index (BMI) 18.0-40.0 kg/m\^2. For Participants With Normal Hepatic Function: Male Participants -Must have been vasectomized or surgically sterilized for at least 4 months or more prior to study intervention administration and agree to the following during the intervention period and for at least 5 days after administration of study intervention, be abstinent from heterosexual intercourse as their preferred and usual lifestyle or must agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant. Female Participants -Is a woman of non-childbearing potential (WONCBP). For Participants With Moderate Hepatic Impairment * Has a diagnosis of chronic (\>6 months), stable (no acute episodes of illness within the previous 30 days from administration of study intervention due to deterioration in hepatic function) hepatic impairment. * Has a score on the Child-Pugh scale of B (a score of 7-9 on Child-Pugh Score) Male Participants -Have been vasectomized or surgically sterilized for at least 4 months or more prior to study intervention administration and agree to the following during the intervention period and for at least 5 days after administration of study intervention, be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent or must agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Female Participants \- Must be a WONCBP.
Exclusion criteria
All Participants: * Is a heavy smoker or heavy user of nicotine-containing products (\>20 cigarettes or equivalent/day). * Consumes greater than 3 glasses of alcoholic beverages or equivalent per day. * Consumes excessive amounts, defined as greater than 6 servings of caffeinated beverages per day. * Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) abuse within the last 2 years. * Presents any concern by the investigator regarding safe participation in the study. For Participants with Normal Hepatic Function * Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases. * Is mentally or legally incapacitated, has significant emotional problems or has a history of clinically significant psychiatric disorder of the last 5 years. * Has a history of cancer (malignancy). * Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs or food. * Is positive for hepatitis B surface antigen (HBsAg), hepatitis C antibodies, or human immunodeficiency virus (HIV). * Had major surgery, donated or lost 1 unit of blood within the last 4 weeks. * Is unable to refrain from or anticipates the use of any medication, including prescription and nonprescription drugs (with the exception of prescription drugs that are approved by the investigator and Sponsor) or herbal remedies for the prohibited period of time. * Has received any nonlive vaccine starting from 14 days prior to study intervention or is scheduled to receive any nonlive vaccine through 30 days following study intervention. Exception: COVID-19 vaccine may be administered. * Has participated in another investigational study within 4 weeks prior to study intervention administration. For Participants With Moderate Hepatic Impairment * Is mentally or legally incapacitated, has significant emotional problems or has a history of clinically significant psychiatric disorder in the last 5 years. * Has a history of cancer (malignancy). * Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs or food. * Has fluctuating or rapidly deteriorating hepatic function. * Has a history of liver or other solid organ transplantation. * Has transjugular intrahepatic portosystemic shunt and/or has undergone portacaval shunting. * Has encephalopathy Grade 3 or worse within 28 days before administration of study intervention. * Is positive for HIV. * Has had major surgery, donated or lost 1 unit of blood within the last 4 weeks. * Is unable to refrain from or anticipates the use of any medication, including prescription and nonprescription drugs (with the exception of prescription drugs that are approved by the investigator and Sponsor) or herbal remedies for the prohibited period of time. * Has received any nonlive vaccine starting from 14 days prior to study intervention or is scheduled to receive any nonlive vaccine through 30 days following study intervention. Exception: COVID-19 vaccine may be administered. * Has participated in another investigational study within 4 weeks prior to study intervention administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24hrs) of Belzutifan | Predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24 hours postdose | AUC0-24hrs was defined as the area under the concentration-time curve of belzutifan from time zero to 24 hours postdose. Blood samples collected predose and at multiple timepoints postdose were used to determine AUC0 to 24 hours of belzutifan. |
| Time to Maximum Plasma Concentration (Tmax) of Belzutifan | Predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 72, 96, and 120 hours postdose | Tmax was defined as the time it took belzutifan to reach its peak level in the blood. Blood samples collected predose and at multiple timepoints postdose were used to determine the Tmax of belzutifan. |
| Apparent Terminal Half-life (t1/2) of Belzutifan | Predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 72, 96, and 120 hours postdose | Apparent terminal half-life (t1/2) was defined as the time needed to reduce the level of belzutifan in the blood by one-half (1/2). Blood samples collected predose and at multiple timepoints postdose were used to determine the apparent terminal half-life (t1/2) of belzutifan. |
| Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-Inf) of Belzutifan | Predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 72, 96, and 120 hours postdose | AUC0-Inf was defined as the area under the concentration-time curve of belzutifan from time zero to infinity. Blood samples collected predose and at multiple timepoints postdose were used to determine AUC0-Inf of belzutifan. |
| Maximum Plasma Concentration (Cmax) of Belzutifan | Predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 72, 96, and 120 hours postdose | Cmax was defined as the peak level belzutifan reaches in the blood. Blood samples collected predose and at multiple timepoints postdose were used to determine Cmax of belzutifan. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Discontinue Study Treatment Due to an AE | Up to 15 days | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued the study due to an AE is reported. |
| Number of Participants Who Experience an Adverse Event (AE) | Up to 15 days | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experienced an AE is reported. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Moderate Hepatic Impairment Participants with moderate hepatic impairment received a single oral 80 mg dose of belzutifan on Day 1. | 9 |
| Healthy Participants with normal hepatic function received a single oral 80 mg dose of belzutifan on Day 1. | 8 |
| Total | 17 |
Baseline characteristics
| Characteristic | Healthy | Total | Moderate Hepatic Impairment |
|---|---|---|---|
| Age, Continuous | 61.4 Years STANDARD_DEVIATION 5.63 | 61.0 Years STANDARD_DEVIATION 4.2 | 60.7 Years STANDARD_DEVIATION 2.69 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 12 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| 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 | 2 Participants | 2 Participants | 0 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 | 6 Participants | 15 Participants | 9 Participants |
| Sex: Female, Male Female | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 8 |
| other Total, other adverse events | 1 / 9 | 1 / 8 |
| serious Total, serious adverse events | 0 / 9 | 0 / 8 |
Outcome results
Primary
Apparent Terminal Half-life (t1/2) of Belzutifan
Apparent terminal half-life (t1/2) was defined as the time needed to reduce the level of belzutifan in the blood by one-half (1/2). Blood samples collected predose and at multiple timepoints postdose were used to determine the apparent terminal half-life (t1/2) of belzutifan.
Time frame: Predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 72, 96, and 120 hours postdose
Population: All participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, who have available measurement data, and have no important protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment | Apparent Terminal Half-life (t1/2) of Belzutifan | 23.5 hr | Geometric Coefficient of Variation 70.5 |
| Healthy | Apparent Terminal Half-life (t1/2) of Belzutifan | 15.4 hr | Geometric Coefficient of Variation 16.4 |
Primary
Area Under the Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24hrs) of Belzutifan
AUC0-24hrs was defined as the area under the concentration-time curve of belzutifan from time zero to 24 hours postdose. Blood samples collected predose and at multiple timepoints postdose were used to determine AUC0 to 24 hours of belzutifan.
Time frame: Predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24 hours postdose
Population: All participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, who have available measurement data, and have no important protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment | Area Under the Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24hrs) of Belzutifan | 10500 ng*hr/mL | Geometric Coefficient of Variation 34.5 |
| Healthy | Area Under the Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24hrs) of Belzutifan | 9650 ng*hr/mL | Geometric Coefficient of Variation 28.8 |
90% CI: [0.84, 1.42]
Primary
Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-Inf) of Belzutifan
AUC0-Inf was defined as the area under the concentration-time curve of belzutifan from time zero to infinity. Blood samples collected predose and at multiple timepoints postdose were used to determine AUC0-Inf of belzutifan.
Time frame: Predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 72, 96, and 120 hours postdose
Population: All participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, who have available measurement data, and have no important protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-Inf) of Belzutifan | 22500 ng*hr/mL | Geometric Coefficient of Variation 80.3 |
| Healthy | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-Inf) of Belzutifan | 14800 ng*hr/mL | Geometric Coefficient of Variation 35.1 |
90% CI: [0.95, 2.43]
Primary
Maximum Plasma Concentration (Cmax) of Belzutifan
Cmax was defined as the peak level belzutifan reaches in the blood. Blood samples collected predose and at multiple timepoints postdose were used to determine Cmax of belzutifan.
Time frame: Predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 72, 96, and 120 hours postdose
Population: All participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, who have available measurement data, and have no important protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment | Maximum Plasma Concentration (Cmax) of Belzutifan | 852 ng/mL | Geometric Coefficient of Variation 28.7 |
| Healthy | Maximum Plasma Concentration (Cmax) of Belzutifan | 870 ng/mL | Geometric Coefficient of Variation 31.4 |
90% CI: [0.76, 1.26]
Primary
Time to Maximum Plasma Concentration (Tmax) of Belzutifan
Tmax was defined as the time it took belzutifan to reach its peak level in the blood. Blood samples collected predose and at multiple timepoints postdose were used to determine the Tmax of belzutifan.
Time frame: Predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 72, 96, and 120 hours postdose
Population: All participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, who have available measurement data, and have no important protocol deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Moderate Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) of Belzutifan | 2.00 hr |
| Healthy | Time to Maximum Plasma Concentration (Tmax) of Belzutifan | 2.00 hr |
Secondary
Number of Participants Who Discontinue Study Treatment Due to an AE
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued the study due to an AE is reported.
Time frame: Up to 15 days
Population: All participants who were allocated and received study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Moderate Hepatic Impairment | Number of Participants Who Discontinue Study Treatment Due to an AE | 0 Participants |
| Healthy | Number of Participants Who Discontinue Study Treatment Due to an AE | 0 Participants |
Secondary
Number of Participants Who Experience an Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experienced an AE is reported.
Time frame: Up to 15 days
Population: All participants who were allocated and received study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Moderate Hepatic Impairment | Number of Participants Who Experience an Adverse Event (AE) | 1 Participants |
| Healthy | Number of Participants Who Experience an Adverse Event (AE) | 1 Participants |