Hepatic Insufficiency
Conditions
Brief summary
The purpose of this study is to evaluate the pharmacokinetics (PK) profile of elbasvir (MK-8742) after a single dose to participants with mild, moderate, or severe hepatic insufficiency compared with healthy controls.
Interventions
DRUGElbasvir
Sponsors
Celerion
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 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Body mass index (BMI) 19 - 40 kg/m\^2, inclusive * In good health based on medical history, physical examination, vital signs, and laboratory safety tests * No clinically significant abnormality on electrocardiogram (ECG) * For participants with hepatic insufficiency only, diagnosis of chronic (\> 6 months), stable (no acute episodes of illness within the previous 2 months due to deterioration in hepatic function) hepatic insufficiency with features of cirrhosis due to any cause * For participants with hepatic insufficiency only, score on the Child-Pugh scale must range from 5 to 6 for mild hepatic insufficiency, from 7 to 9 for moderate hepatic insufficiency, and from 10 to 15 for severe hepatic insufficiency * Females of childbearing potential must be either be sexually inactive (abstinent) for 14 days before study drug administration and throughout the study or be using an acceptable method of birth control * Females of non-childbearing potential must have undergone sterilization procedures at least 6 months before Study Day 1 * Non-vasectomized males must agree to use a condom with spermicide or abstain from sexual intercourse during the study and for 3 months after study drug administration * Ability to swallow multiple capsules
Exclusion criteria
* Previously enrolled in this study * Mentally or legally incapacitated, significant emotional problems at the time of screening or expected during the conduct of the study, or a history of a clinically significant psychiatric disorder over the last 5 years * History or presence of significant cardiovascular, pulmonary, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurological disease * History of any illness that might confound the results of the study or pose an additional risk to the participant by participating in the study * For participants with hepatic insufficiency only, estimated creatinine clearance (CrCl) ≤30 mL/min based on the Cockcroft-Gault equation at screening * History or presence of drug abuse within the past 2 years * For healthy participants only, history of alcoholism within the past 2 years * Females who are pregnant or lactating * Positive results for the urine drug screen at screening or check-in * Positive results at screening or history of human immunodeficiency virus (HIV) or untreated hepatitis C virus (HCV); HCV ribonucleic acid (RNA)-negative participants documented to be cured following anti-HCV treatment are eligible * For healthy participants only, positive results at screening for hepatitis B surface antigen (HBsAg) * Use of any drugs or substances known to be strong inhibitors of cytochrome P450 3A4 (CYP3A4) enzymes and/or P-glycoprotein (P-gp) or any inhibitors of organic anion transporting peptide 1B (OATP1B) within 14 days or 5-times the half-life of the product (for healthy participants) or which cannot be discontinued at least 14 days or 5 times the half-life of the product (for hepatic insufficiency participants) before study drug administration and throughout the study * Use of any drugs or substances known to be strong inducers of CYP3A4 enzymes and/or P-gp, including St-John's Wort or rifampin, within 28 days or 5 times the half-life of the product before study drug administration * Currently use of any medication or substance which cannot be discontinued or maintained at a steady dose and regimen at least 14 days before study drug administration and throughout the study * For healthy participants only, on a special diet within 28 days before study drug administration * Blood donation \>500 mL or significant blood loss within 56 days before study drug administration * Plasma donation within 7 days before study drug administration * Participation in another clinical study within 28 days before study drug administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From 0 to Infinity (AUC0-inf) of Elbasvir | Predose and Hours 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 96, 144, and 168 | Blood samples were collected at predose and Hours 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 96, 144, and 168 to determine the AUC0-inf of elbasvir. |
| Area Under the Curve From 0 to 24 Hours (AUC0-24hr) of Elbasvir | Predose and Hours 0.5, 1, 2, 3, 4, , 6, 8, 12, 16, and 24 | Blood samples were collected at predose and Hours 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 24 to determine the AUC0-24hr of elbasvir. |
| Maximum Concentration (Cmax) of Elbasvir | Predose and Hours 0.5, 1, 2, 3, 4, , 6, 8, 12, 16, 24, 48, 96, 144, and 168 | Blood samples were collected at predose and Hours 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 96, 144, and 168 to determine the Cmax of Elbasvir. |
| Concentration at 24 Hours (C24) After Dosing Elbasvir | Hour 24 | Blood samples were collected at predose and Hours 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 24, to determine the concentration of elbasvir at Hour 24 was determined. |
| Time to Maximum Concentration (Tmax) of Elbasvir | Predose and Hours 0.5, 1, 2, 3, 4, , 6, 8, 12, 16, 24, 48, 96, 144, and 168 | Blood samples were collected at predose and Hours 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 96, 144, and 168 to determine the maximum concentration (Cmax) of elbasvir. The time to reach Cmax (Tmax) was determined. |
| Apparent Terminal Half-Life (t1/2) of Elbasvir | Predose and Hours 0.5, 1, 2, 3, 4, , 6, 8, 12, 16, 24, 48, 96, 144, and 168 | Blood samples were collected at predose and Hours 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 96, 144, and 168 to determine the t1/2 of elbasvir. |
Countries
United States
Participant flow
Pre-assignment details
3 participants from the mild insufficiency arm were mistakenly reenrolled into the moderate arm and received a 2nd single dose of study drug. Data for these 3 participants were excluded from pharmacokinetic analysis of the moderate arm but were included in the safety analysis. An additional 3 participants were enrolled in the moderate arm.
Participants by arm
| Arm | Count |
|---|---|
| Mild Hepatic Insufficiency Single oral dose of 5 x 10 mg capsules of elbasvir administered to participants with mild hepatic insufficiency, defined as a score of 5 to 6 on the Child-Pugh scale | 8 |
| Moderate Hepatic Insufficiency Single oral dose of 5 x 10 mg capsules of elbasvir administered to participants with moderate hepatic insufficiency, defined as a score of 7 to 9 on the Child-Pugh scale | 11 |
| Severe Hepatic Insufficiency Single oral dose of 5 x 10 mg capsules of elbasvir administered to participants with severe hepatic insufficiency, defined as a score of 10 to 15 on the Child-Pugh scale | 7 |
| Healthy Participants Single oral dose of 5 x 10 mg capsules of elbasvir administered to participants matched to the mean of all hepatic insufficiency participants for age, gender, and weight | 8 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Mild Hepatic Insufficiency | Moderate Hepatic Insufficiency | Severe Hepatic Insufficiency | Healthy Participants | Total |
|---|---|---|---|---|---|
| Age, Continuous | 54 Years | 54 Years | 56 Years | 54 Years | 54.35 Years |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 4 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 8 Participants | 10 Participants | 3 Participants | 6 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 8 | 3 / 11 | 0 / 7 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 1 / 11 | 0 / 7 | 0 / 8 |
Outcome results
Primary
Apparent Terminal Half-Life (t1/2) of Elbasvir
Blood samples were collected at predose and Hours 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 96, 144, and 168 to determine the t1/2 of elbasvir.
Time frame: Predose and Hours 0.5, 1, 2, 3, 4, , 6, 8, 12, 16, 24, 48, 96, 144, and 168
Population: Participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment and had available data for the endpoint. Moderate arm summary excludes data for 3 participants incorrectly re-enrolled and dosed in moderate arm after completing dosing and follow-up in the mild insufficiency arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatic Insufficiency | Apparent Terminal Half-Life (t1/2) of Elbasvir | 24.80 hr | Geometric Coefficient of Variation 21.65 |
| Moderate Hepatic Insufficiency | Apparent Terminal Half-Life (t1/2) of Elbasvir | 25.39 hr | Geometric Coefficient of Variation 34.24 |
| Severe Hepatic Insufficiency | Apparent Terminal Half-Life (t1/2) of Elbasvir | 33.72 hr | Geometric Coefficient of Variation 20.82 |
| Healthy Participants | Apparent Terminal Half-Life (t1/2) of Elbasvir | 20.74 hr | Geometric Coefficient of Variation 12.64 |
Primary
Area Under the Curve From 0 to 24 Hours (AUC0-24hr) of Elbasvir
Blood samples were collected at predose and Hours 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 24 to determine the AUC0-24hr of elbasvir.
Time frame: Predose and Hours 0.5, 1, 2, 3, 4, , 6, 8, 12, 16, and 24
Population: Participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment and had available data for the endpoint. Moderate arm summary excludes data for 3 participants incorrectly re-enrolled and dosed in moderate arm after completing dosing and follow-up in the mild insufficiency arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Mild Hepatic Insufficiency | Area Under the Curve From 0 to 24 Hours (AUC0-24hr) of Elbasvir | 0.87 μM•hr |
| Moderate Hepatic Insufficiency | Area Under the Curve From 0 to 24 Hours (AUC0-24hr) of Elbasvir | 0.92 μM•hr |
| Severe Hepatic Insufficiency | Area Under the Curve From 0 to 24 Hours (AUC0-24hr) of Elbasvir | 0.92 μM•hr |
| Healthy Participants | Area Under the Curve From 0 to 24 Hours (AUC0-24hr) of Elbasvir | 1.45 μM•hr |
Comparison: Back-transformed least-squares mean and confidence interval from linear fixed effect model performed on natural log-transformed values90% CI: [0.34, 1.05]
Comparison: Back-transformed least-squares mean and confidence interval from linear fixed effect model performed on natural log-transformed values90% CI: [0.35, 1.14]
Comparison: Back-transformed least-squares mean and confidence interval from linear fixed effect model performed on natural log-transformed values90% CI: [0.35, 1.13]
Primary
Area Under the Curve From 0 to Infinity (AUC0-inf) of Elbasvir
Blood samples were collected at predose and Hours 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 96, 144, and 168 to determine the AUC0-inf of elbasvir.
Time frame: Predose and Hours 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 96, 144, and 168
Population: Participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment and had available data for the endpoint. Moderate arm summary excludes data for 3 participants incorrectly re-enrolled and dosed in moderate arm after completing dosing and follow-up in the mild insufficiency arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Mild Hepatic Insufficiency | Area Under the Curve From 0 to Infinity (AUC0-inf) of Elbasvir | 1.56 μM•hr |
| Moderate Hepatic Insufficiency | Area Under the Curve From 0 to Infinity (AUC0-inf) of Elbasvir | 1.86 μM•hr |
| Severe Hepatic Insufficiency | Area Under the Curve From 0 to Infinity (AUC0-inf) of Elbasvir | 2.28 μM•hr |
| Healthy Participants | Area Under the Curve From 0 to Infinity (AUC0-inf) of Elbasvir | 2.58 μM•hr |
Comparison: Back-transformed least-squares mean and confidence interval from linear fixed effect model performed on natural log-transformed values90% CI: [0.34, 1.08]
Comparison: Back-transformed least-squares mean and confidence interval from linear fixed effect model performed on natural log-transformed values90% CI: [0.4, 1.31]
Comparison: Back-transformed least-squares mean and confidence interval from linear fixed effect model performed on natural log-transformed values90% CI: [0.48, 1.61]
Primary
Concentration at 24 Hours (C24) After Dosing Elbasvir
Blood samples were collected at predose and Hours 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 24, to determine the concentration of elbasvir at Hour 24 was determined.
Time frame: Hour 24
Population: Participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment and had available data for the endpoint. Moderate arm summary excludes data for 3 participants incorrectly re-enrolled and dosed in moderate arm after completing dosing and follow-up in the mild insufficiency arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Mild Hepatic Insufficiency | Concentration at 24 Hours (C24) After Dosing Elbasvir | 22.9 nM |
| Moderate Hepatic Insufficiency | Concentration at 24 Hours (C24) After Dosing Elbasvir | 25.9 nM |
| Severe Hepatic Insufficiency | Concentration at 24 Hours (C24) After Dosing Elbasvir | 29.6 nM |
| Healthy Participants | Concentration at 24 Hours (C24) After Dosing Elbasvir | 37.7 nM |
Comparison: Back-transformed least-squares mean and confidence interval from linear fixed effect model performed on natural log-transformed values90% CI: [0.34, 1.08]
Comparison: Back-transformed least-squares mean and confidence interval from linear fixed effect model performed on natural log-transformed values90% CI: [0.38, 1.25]
Comparison: Back-transformed least-squares mean and confidence interval from linear fixed effect model performed on natural log-transformed values90% CI: [0.43, 1.43]
Primary
Maximum Concentration (Cmax) of Elbasvir
Blood samples were collected at predose and Hours 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 96, 144, and 168 to determine the Cmax of Elbasvir.
Time frame: Predose and Hours 0.5, 1, 2, 3, 4, , 6, 8, 12, 16, 24, 48, 96, 144, and 168
Population: Participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment and had available data for the endpoint. Moderate arm summary excludes data for 3 participants incorrectly re-enrolled and dosed in moderate arm after completing dosing and follow-up in the mild insufficiency arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Mild Hepatic Insufficiency | Maximum Concentration (Cmax) of Elbasvir | 70.1 nM |
| Moderate Hepatic Insufficiency | Maximum Concentration (Cmax) of Elbasvir | 83.0 nM |
| Severe Hepatic Insufficiency | Maximum Concentration (Cmax) of Elbasvir | 70.7 nM |
| Healthy Participants | Maximum Concentration (Cmax) of Elbasvir | 121.0 nM |
Comparison: Back-transformed least-squares mean and confidence interval from linear fixed effect model performed on natural log-transformed values90% CI: [0.32, 1.05]
Comparison: Back-transformed least-squares mean and confidence interval from linear fixed effect model performed on natural log-transformed values90% CI: [0.35, 1.14]
Comparison: Back-transformed least-squares mean and confidence interval from linear fixed effect model performed on natural log-transformed values90% CI: [0.32, 1.08]
Primary
Time to Maximum Concentration (Tmax) of Elbasvir
Blood samples were collected at predose and Hours 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 96, 144, and 168 to determine the maximum concentration (Cmax) of elbasvir. The time to reach Cmax (Tmax) was determined.
Time frame: Predose and Hours 0.5, 1, 2, 3, 4, , 6, 8, 12, 16, 24, 48, 96, 144, and 168
Population: Participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment and had available data for the endpoint. Moderate arm summary excludes data for 3 participants incorrectly re-enrolled and dosed in moderate arm after completing dosing and follow-up in the mild insufficiency arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mild Hepatic Insufficiency | Time to Maximum Concentration (Tmax) of Elbasvir | 3.50 hour (hr) |
| Moderate Hepatic Insufficiency | Time to Maximum Concentration (Tmax) of Elbasvir | 3.50 hour (hr) |
| Severe Hepatic Insufficiency | Time to Maximum Concentration (Tmax) of Elbasvir | 4.00 hour (hr) |
| Healthy Participants | Time to Maximum Concentration (Tmax) of Elbasvir | 3.50 hour (hr) |