Hepatic Impairment
Conditions
Keywords
Hepatic Impairment, Sotorasib
Brief summary
The main purpose of the study is to evaluate the pharmacokinetics (PK) of a single oral dose of sotorasib administered in participants with moderate or severe hepatic impairment compared to participants with normal hepatic function.
Interventions
DRUGSotorasib
Sotorasib will be administered as an oral tablet.
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria All Participants * Participant has provided informed consent before initiation of any study-specific activities/procedures * Participants between 18 and 70 years of age * Body mass index between 18 and 38 kg/m\^2 * Females of nonchildbearing potential defined as permanently sterile or postmenopausal Participants with Normal Hepatic Function * In good health, determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory evaluations Participants with Hepatic Impairment * Child-Pugh B or C classification with clinical laboratory values and clinical examination findings * Documented medical history of chronic liver disease Key
Exclusion criteria
All Participants * Female participants with a positive pregnancy test at Screening or Check-in * Male participants with a pregnant partner or partner planning to become pregnant who are unwilling to practice abstinence or use a condom for 7 days after dosing * History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance * Participant has received a dose of an investigational drug (new chemical entity) within the past 30 days or 5 half-lives, whichever is longer, prior to Check-in * Use of any over-the-counter or prescription medications within 30 days or 5 half-lives (whichever is longer) * All herbal medicines vitamins, and supplements consumed by the subject within the 30 days prior to enrollment * Alcohol consumption from 48 hours prior to Check-in * Positive test for illicit drugs, cotinine (tobacco or nicotine use), and/or alcohol use at Check-in * Positive human immunodeficiency virus test at Screening Participants with Normal Hepatic Function * Positive hepatitis B or hepatitis C panel at Screening. Subjects whose results are compatible with prior immunity (vaccination or prior infection) may be included * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> upper limit of normal (ULN) at Screening or Check-in * Total bilirubin levels \> ULN at Screening or Check-in * A QT interval corrected for heart rate based on the Fridericia correction (QTcF) interval \> 450 msec in male subjects or \> 470 msec in female subjects or history/evidence of long QT syndrome at Screening or Check-in, confirmed by calculating the mean of the original value and 2 repeats Participants with Hepatic Impairment * Values outside the normal range for liver function tests that are not consistent with their hepatic condition, as determined by the Investigator (or designee) * A QTcF interval \> 470 msec in male subjects or \> 480 msec in female subjects at Screening or Check-in, confirmed by calculating the mean of the original value and 2 repeats * Use of a new medication, or a change in dose, for the treatment, or worsening of, hepatic encephalopathy within 30 days prior to Check-in * Presence of a portosystemic shunt * Evidence of severe ascites
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Sotorasib | Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1 |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of Sotorasib | Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1 |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Sotorasib | Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Unbound Apparent Total Plasma Clearance (CLu/F) of Sotorasib | Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1 | — |
| Unbound Apparent Volume of Distribution During the Terminal Phase (Vz,u/F) of Sotorasib | Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1 | — |
| Unbound Cmax (Cmax,u) of Sotorasib | Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1 | — |
| Number of Participants Who Experienced One or More Treatment Emergent Adverse Events (TEAEs) | Day 1 to Day 8 | TEAEs were defined as any adverse events (AEs) that started during or after dosing, or started prior to dosing and increased in severity after dosing. Any clinically significant changes in clinical laboratory evaluations, 12-lead electrocardiograms (ECGs) and vital signs were also reported as TEAEs. |
| Unbound AUClast (AUClast,u) of Sotorasib | Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1 | — |
| Unbound AUCinf (AUCinf,u) of Sotorasib | Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1 | — |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at research centers in the United States from April 2021 to March 2022.
Participants by arm
| Arm | Count |
|---|---|
| Normal Hepatic Function Participants with normal hepatic function (no impairment) received a single oral 960 mg dose of sotorasib under fasted conditions. | 7 |
| Moderate Hepatic Impairment Participants with moderate hepatic function (Child-Pugh Class B at screening) received a single oral 960 mg dose of sotorasib under fasted conditions. | 8 |
| Severe Hepatic Impairment Participants with severe hepatic function (Child-Pugh Class C at screening) received a single oral 960 mg dose of sotorasib under fasted conditions. | 5 |
| Total | 20 |
Baseline characteristics
| Characteristic | Moderate Hepatic Impairment | Severe Hepatic Impairment | Total | Normal Hepatic Function |
|---|---|---|---|---|
| Age, Continuous | 58.5 years STANDARD_DEVIATION 5.66 | 51.6 years STANDARD_DEVIATION 7.37 | 57.0 years STANDARD_DEVIATION 7.1 | 59.0 years STANDARD_DEVIATION 7.35 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 3 Participants | 13 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 2 Participants | 7 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 4 Participants | 18 Participants | 6 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 9 Participants | 3 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 11 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 8 | 0 / 5 |
| other Total, other adverse events | 1 / 7 | 2 / 8 | 1 / 5 |
| serious Total, serious adverse events | 0 / 7 | 0 / 8 | 0 / 5 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Sotorasib
Time frame: Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Sotorasib | 29000 h*ng/mL | Geometric Coefficient of Variation 86.4 |
| Moderate Hepatic Impairment | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Sotorasib | 21700 h*ng/mL | Geometric Coefficient of Variation 58.2 |
| Severe Hepatic Impairment | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Sotorasib | 30100 h*ng/mL | Geometric Coefficient of Variation 12.2 |
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of Sotorasib
Time frame: Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of Sotorasib | 28700 h*ng/mL | Geometric Coefficient of Variation 87.8 |
| Moderate Hepatic Impairment | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of Sotorasib | 21500 h*ng/mL | Geometric Coefficient of Variation 58.2 |
| Severe Hepatic Impairment | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of Sotorasib | 29900 h*ng/mL | Geometric Coefficient of Variation 12.6 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Sotorasib
Time frame: Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Maximum Observed Plasma Concentration (Cmax) of Sotorasib | 5080 ng/mL | Geometric Coefficient of Variation 108.5 |
| Moderate Hepatic Impairment | Maximum Observed Plasma Concentration (Cmax) of Sotorasib | 4850 ng/mL | Geometric Coefficient of Variation 60.6 |
| Severe Hepatic Impairment | Maximum Observed Plasma Concentration (Cmax) of Sotorasib | 7250 ng/mL | Geometric Coefficient of Variation 15.7 |
Secondary
Number of Participants Who Experienced One or More Treatment Emergent Adverse Events (TEAEs)
TEAEs were defined as any adverse events (AEs) that started during or after dosing, or started prior to dosing and increased in severity after dosing. Any clinically significant changes in clinical laboratory evaluations, 12-lead electrocardiograms (ECGs) and vital signs were also reported as TEAEs.
Time frame: Day 1 to Day 8
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normal Hepatic Function | Number of Participants Who Experienced One or More Treatment Emergent Adverse Events (TEAEs) | 1 Participants |
| Moderate Hepatic Impairment | Number of Participants Who Experienced One or More Treatment Emergent Adverse Events (TEAEs) | 2 Participants |
| Severe Hepatic Impairment | Number of Participants Who Experienced One or More Treatment Emergent Adverse Events (TEAEs) | 1 Participants |
Secondary
Unbound Apparent Total Plasma Clearance (CLu/F) of Sotorasib
Time frame: Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Unbound Apparent Total Plasma Clearance (CLu/F) of Sotorasib | 1290 L/h | Geometric Coefficient of Variation 156.7 |
| Moderate Hepatic Impairment | Unbound Apparent Total Plasma Clearance (CLu/F) of Sotorasib | 715 L/h | Geometric Coefficient of Variation 69.6 |
| Severe Hepatic Impairment | Unbound Apparent Total Plasma Clearance (CLu/F) of Sotorasib | 205 L/h | Geometric Coefficient of Variation 29.4 |
Secondary
Unbound Apparent Volume of Distribution During the Terminal Phase (Vz,u/F) of Sotorasib
Time frame: Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Unbound Apparent Volume of Distribution During the Terminal Phase (Vz,u/F) of Sotorasib | 7080 liters | Geometric Coefficient of Variation 275.6 |
| Moderate Hepatic Impairment | Unbound Apparent Volume of Distribution During the Terminal Phase (Vz,u/F) of Sotorasib | 3820 liters | Geometric Coefficient of Variation 115.2 |
| Severe Hepatic Impairment | Unbound Apparent Volume of Distribution During the Terminal Phase (Vz,u/F) of Sotorasib | 928 liters | Geometric Coefficient of Variation 39.1 |
Secondary
Unbound AUCinf (AUCinf,u) of Sotorasib
Time frame: Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Unbound AUCinf (AUCinf,u) of Sotorasib | 742 h*ng/mL | Geometric Coefficient of Variation 156.7 |
| Moderate Hepatic Impairment | Unbound AUCinf (AUCinf,u) of Sotorasib | 1340 h*ng/mL | Geometric Coefficient of Variation 69.6 |
| Severe Hepatic Impairment | Unbound AUCinf (AUCinf,u) of Sotorasib | 4680 h*ng/mL | Geometric Coefficient of Variation 29.4 |
Secondary
Unbound AUClast (AUClast,u) of Sotorasib
Time frame: Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Unbound AUClast (AUClast,u) of Sotorasib | 694 h*ng/mL | Geometric Coefficient of Variation 146.3 |
| Moderate Hepatic Impairment | Unbound AUClast (AUClast,u) of Sotorasib | 1320 h*ng/mL | Geometric Coefficient of Variation 71 |
| Severe Hepatic Impairment | Unbound AUClast (AUClast,u) of Sotorasib | 4680 h*ng/mL | Geometric Coefficient of Variation 29.4 |
Secondary
Unbound Cmax (Cmax,u) of Sotorasib
Time frame: Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Unbound Cmax (Cmax,u) of Sotorasib | 183 ng/mL | Geometric Coefficient of Variation 240.8 |
| Moderate Hepatic Impairment | Unbound Cmax (Cmax,u) of Sotorasib | 400 ng/mL | Geometric Coefficient of Variation 110.9 |
| Severe Hepatic Impairment | Unbound Cmax (Cmax,u) of Sotorasib | 1220 ng/mL | Geometric Coefficient of Variation 9.8 |