Hepatic Failure, Hepatic Impairment, Chronic Hepatitis C Infection With Hepatic Coma
Conditions
Keywords
Hepatic, Hepatitis C Virus, Suboxone, Buprenorphine, Naloxone
Brief summary
The objective was to determine if hepatitis C virus (HCV) infection or mild to severe hepatic impairment (Child-Pugh Classes A, B, and C) altered the PK of buprenorphine, norbuprenorphine, or naloxone.
Detailed description
This will be a multi-center, open-label study. After providing informed consent, subjects will undergo an outpatient screening period of up to 21 days. Screening procedures will include an assessment of mental status which will be repeated before dosing. Eligible subjects will then undergo hospital intake procedures and reside at the investigational site until Day 5. Subjects will be enrolled in 5-treatment groups as follows: (1) Group 1: Subjects with hepatic impairment classified as Child-Pugh A; (2) Group 2: Subjects with hepatic impairment classified as Child-Pugh B; (3) Group 3: Subjects with hepatic impairment classified as Child-Pugh C; (4) Group 4: Subjects with Hepatitis C Virus (HCV) infection but without hepatic impairment; and (5) Group 5: Subjects without hepatic disease or impairment. Group 5 is used as a control group
Interventions
DRUG2.0mg Buprenorphine/0.5mg Naloxone
Each participant received a single sublingual dose of Suboxone® on Day 1 following a fast of at least 8 hours prior to dosing and 2 hours after dosing.
DRUGPromethazine
Each participant received a 25-mg or 50-mg promethazine oral dose 30 minutes before Suboxone® administration and then 25-mg promethazine orally or by rectal suppositories every 4 hours as needed for nausea and vomiting during the first 48 hours after Suboxone® administration.
Sponsors
Indivior Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Males or females between the ages of 18 and 65 years, inclusive * Females should be surgically sterile, 2 years post-menopausal or have a negative plasma β-human chorionic gonadotropin (β-hCG) pregnancy test. Subjects of child-bearing potential must take reasonable precautions during the study to avoid pregnancy by agreeing to remain abstinent or to practice double-barrier forms of birth control from the time of informed consent through the last study visit. A negative plasma pregnancy (β-hCG) test at Screening and upon admission to the investigational site. Testing for β-hCG will need to be timed to ensure a negative pregnancy result at Day 1. * Male subject agrees to use barrier contraception and spermicide when engaging in sexual activity with a female of child-bearing potential for at least 28 days after the study medication dose. * Male subject agrees to refrain from sperm donations for the entire duration of the study and for at least 90 days after the study drug dose. * Body mass index (BMI) of ≥ 18 to ≤ 33 kg\^m2. * Subject agrees to the conditions of the study and signs the informed consent form
Exclusion criteria
* Medical conditions: (a) pregnancy; and (b) breastfeeding * Psychiatric conditions: (a) current treatment for opioid addiction with substitution therapies; (b) active history of bipolar I, bipolar II, schizophrenia, schizophreniform; schizoaffective; mania, hypomania, or severe post-traumatic stress disorder; and (c) presence of suicidal behavior within the year before informed consent or suicidal intent within the 30 days before informed consent as documented by the Columbia Suicide Severity Rating Scale * Hypersensitivity to opioids, defined as intractable vomiting, severe constipation, or severe pruritus after opioid treatment * Subject has a known intolerance or hypersensitivity to buprenorphine or naloxone or any excipients in the Suboxone tablet formulation * In the judgment of the investigator, any other condition that would preclude safe, useful, or consistent participation in the study * Use of any investigational medication or investigational medical device in the 30 days before informed consent * Hepatic encephalopathy greater than West Haven Grade 2 * Donation of \> 250 ml of blood within previous 30 days * Systolic BP ≤ 90 or ≥ 160 mmHg and/or Diastolic BP \< 60 mmHg or \> 100 mmHg * History of cholecystectomy * History or current acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus (HIV) antibodies * Estimated creatinine clearance rate (eC Cr) using Cockcroft-Gault formula \< 60 mL/min * More than 1 missed appointment during Screening * Currently under mandate by the criminal justice system or Child and Family Services to participate in drug abuse treatment * Participation in drug or alcohol dependence treatment in the 30 days before informed consent * Positive urine drug screen result for amphetamines, methamphetamine, barbiturates, benzodiazepines, buprenorphine, cannabinoids, cocaine, methadone, opioids, oxycodone, or phencyclidine which, in the judgment of the investigator, is indicative of non-prescribed drug use; and/or positive urine alcohol screen result in which, in the judgment of the investigator, is indicative of alcohol abuse or alcoholism * Consumption of prohibited medications within 1 week of informed consent, including buprenorphine * Consumption of grapefruit and grapefruit juice for at least one week before the study dose and until the end of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing | AUC0-last was calculated for buprenorphine, norbuprenorphine, naloxone, and naloxone-3-β-D-glucuronide using non-compartmental analysis: AUC0-last = AUC from time 0 to the time of the last measurable plasma concentration, calculated using the linear trapezoidal rule. |
| Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing | — |
| Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing | The extrapolation to infinity was done using the terminal phase. AUC0-inf = AUC0-last + Ct/λz Where Ct was the last observed quantifiable concentration and λz was the apparent terminal phase elimination rate constant. |
| Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing | — |
| Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing | — |
| Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing | Calculated as: (AUC0-inf - AUC0-last)/AUC0-inf \* 100 AUC0-inf, apparent body clearance (CL/F), and apparent volume of distribution during terminal phase (Vz/F) would not have been reported if %AUCextrap was \> 20%. |
| Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing | For the determination of λz, only those data points judged to describe the terminal log-linear decline resulting in an adjusted coefficient of determination value (R2) \> 0.7 were used in the regression. A minimum of 3 data points were used in calculating λz. |
| Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing | Terminal elimination half-life, calculated as ln(2)/λz. The terminal phase elimination half-life was calculated over a period of at least 2 half-lives. |
| Apparent Body Clearance (CL/F) of Buprenorphine and Naloxone | before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing | Apparent body clearance (only for buprenorphine and naloxone), calculated as Dose/AUC0-inf. |
| Apparent Volume of Distribution During Terminal Phase (Vz/F) of Buprenorphine and Naloxone | before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing | Apparent volume of distribution during terminal phase (only for buprenorphine and naloxone), calculated as Dose/(λz • AUC0-inf). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Hepatic Impairment: Child-Pugh A Participants with chronic liver disease and classified as Child-Pugh Grade A had a score of 5-6 (out of 15) which correlates with a good prognosis. Each participant received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1. | 9 |
| Hepatic Impairment: Child-Pugh B Participants with chronic liver disease and classified as Child-Pugh Grade B had a score of 7-9 (out of 15) which correlates with significant functional liver compromise. Each participant received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1. | 8 |
| Hepatic Impairment: Child-Pugh C Participants with chronic liver disease and classified as Child-Pugh Grade C had a score of 10-15 (out of 15) which correlates with decompensated liver disease. Each participant received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1. | 8 |
| HCV Without Hepatic Impairment Participants with hepatitis C virus (HCV) without hepatic impairment received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1. | 10 |
| No Hepatic Disease or Impairment Participants with no hepatic disease or impairment received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1. | 8 |
| Total | 43 |
Baseline characteristics
| Characteristic | Hepatic Impairment: Child-Pugh A | Hepatic Impairment: Child-Pugh B | Hepatic Impairment: Child-Pugh C | HCV Without Hepatic Impairment | No Hepatic Disease or Impairment | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 58.0 years | 58.6 years | 53.9 years | 53.0 years | 57.1 years | 56.0 years |
| Body Mass Index | 25.5 kg/m^2 | 27.0 kg/m^2 | 27.9 kg/m^2 | 26.2 kg/m^2 | 29.3 kg/m^2 | 27.1 kg/m^2 |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 0 participants | 1 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants | 1 participants | 0 participants | 1 participants | 1 participants | 5 participants |
| Race/Ethnicity, Customized White | 6 participants | 7 participants | 8 participants | 8 participants | 7 participants | 36 participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 1 Participants | 6 Participants | 4 Participants | 18 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 7 Participants | 4 Participants | 4 Participants | 25 Participants |
| Weight | 74.2 kg | 75.4 kg | 82.2 kg | 74.7 kg | 76.6 kg | 76.5 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 9 | 7 / 8 | 6 / 8 | 10 / 10 | 8 / 8 |
| serious Total, serious adverse events | 0 / 9 | 0 / 8 | 0 / 8 | 0 / 10 | 0 / 8 |
Outcome results
Primary
Apparent Body Clearance (CL/F) of Buprenorphine and Naloxone
Apparent body clearance (only for buprenorphine and naloxone), calculated as Dose/AUC0-inf.
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK population included participants without any major protocol deviations who contributed PK samples and had sufficient evaluable data for the calculation of PK parameters. Eight enrolled participants were excluded due to emesis observed within 4 hours postdose, and two due to protocol violations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Hepatic Impairment: Child-Pugh A | Apparent Body Clearance (CL/F) of Buprenorphine and Naloxone | Buprenorphine (5,4,5,3,6) | 182 L/hr | Geometric Coefficient of Variation 30.8 |
| Hepatic Impairment: Child-Pugh A | Apparent Body Clearance (CL/F) of Buprenorphine and Naloxone | Naloxone (5,6,5,4,7) | 7448 L/hr | Geometric Coefficient of Variation 18.7 |
| Hepatic Impairment: Child-Pugh B | Apparent Body Clearance (CL/F) of Buprenorphine and Naloxone | Buprenorphine (5,4,5,3,6) | 106 L/hr | Geometric Coefficient of Variation 58.4 |
| Hepatic Impairment: Child-Pugh B | Apparent Body Clearance (CL/F) of Buprenorphine and Naloxone | Naloxone (5,6,5,4,7) | 1824 L/hr | Geometric Coefficient of Variation 195 |
| Hepatic Impairment: Child-Pugh C | Apparent Body Clearance (CL/F) of Buprenorphine and Naloxone | Buprenorphine (5,4,5,3,6) | 78.3 L/hr | Geometric Coefficient of Variation 44.6 |
| Hepatic Impairment: Child-Pugh C | Apparent Body Clearance (CL/F) of Buprenorphine and Naloxone | Naloxone (5,6,5,4,7) | 344 L/hr | Geometric Coefficient of Variation 57 |
| HCV Without Hepatic Impairment | Apparent Body Clearance (CL/F) of Buprenorphine and Naloxone | Naloxone (5,6,5,4,7) | 5874 L/hr | Geometric Coefficient of Variation 57 |
| HCV Without Hepatic Impairment | Apparent Body Clearance (CL/F) of Buprenorphine and Naloxone | Buprenorphine (5,4,5,3,6) | 232 L/hr | Geometric Coefficient of Variation 22.6 |
| No Hepatic Disease or Impairment | Apparent Body Clearance (CL/F) of Buprenorphine and Naloxone | Buprenorphine (5,4,5,3,6) | 193 L/hr | Geometric Coefficient of Variation 56 |
| No Hepatic Disease or Impairment | Apparent Body Clearance (CL/F) of Buprenorphine and Naloxone | Naloxone (5,6,5,4,7) | 5148 L/hr | Geometric Coefficient of Variation 53.4 |
Primary
Apparent Volume of Distribution During Terminal Phase (Vz/F) of Buprenorphine and Naloxone
Apparent volume of distribution during terminal phase (only for buprenorphine and naloxone), calculated as Dose/(λz • AUC0-inf).
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK population included participants without any major protocol deviations who contributed PK samples and had sufficient evaluable data for the calculation of PK parameters. Eight enrolled participants were excluded due to emesis observed within 4 hours postdose, and two due to protocol violations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Hepatic Impairment: Child-Pugh A | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Buprenorphine and Naloxone | Buprenorphine (5,4,5,3,6) | 7226 Liters | Geometric Coefficient of Variation 26.1 |
| Hepatic Impairment: Child-Pugh A | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Buprenorphine and Naloxone | Naloxone (5,6,5,4,7) | 23150 Liters | Geometric Coefficient of Variation 28.1 |
| Hepatic Impairment: Child-Pugh B | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Buprenorphine and Naloxone | Buprenorphine (5,4,5,3,6) | 6959 Liters | Geometric Coefficient of Variation 42.6 |
| Hepatic Impairment: Child-Pugh B | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Buprenorphine and Naloxone | Naloxone (5,6,5,4,7) | 14353 Liters | Geometric Coefficient of Variation 187 |
| Hepatic Impairment: Child-Pugh C | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Buprenorphine and Naloxone | Buprenorphine (5,4,5,3,6) | 6373 Liters | Geometric Coefficient of Variation 28.9 |
| Hepatic Impairment: Child-Pugh C | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Buprenorphine and Naloxone | Naloxone (5,6,5,4,7) | 2272 Liters | Geometric Coefficient of Variation 66.7 |
| HCV Without Hepatic Impairment | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Buprenorphine and Naloxone | Naloxone (5,6,5,4,7) | 15845 Liters | Geometric Coefficient of Variation 97.9 |
| HCV Without Hepatic Impairment | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Buprenorphine and Naloxone | Buprenorphine (5,4,5,3,6) | 9580 Liters | Geometric Coefficient of Variation 29.1 |
| No Hepatic Disease or Impairment | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Buprenorphine and Naloxone | Buprenorphine (5,4,5,3,6) | 9176 Liters | Geometric Coefficient of Variation 21.9 |
| No Hepatic Disease or Impairment | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Buprenorphine and Naloxone | Naloxone (5,6,5,4,7) | 15294 Liters | Geometric Coefficient of Variation 42.8 |
Primary
Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
The extrapolation to infinity was done using the terminal phase. AUC0-inf = AUC0-last + Ct/λz Where Ct was the last observed quantifiable concentration and λz was the apparent terminal phase elimination rate constant.
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK population included participants without any major protocol deviations who contributed PK samples and had sufficient evaluable data for the calculation of PK parameters. Eight enrolled participants were excluded due to emesis observed within 4 hours postdose, and two due to protocol violations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Hepatic Impairment: Child-Pugh A | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (5,4,5,3,6) | 11.0 ng*hr/mL | Geometric Coefficient of Variation 30.8 |
| Hepatic Impairment: Child-Pugh A | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (3,3,1,3,3) | 25.4 ng*hr/mL | Geometric Coefficient of Variation 25.5 |
| Hepatic Impairment: Child-Pugh A | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 0.0671 ng*hr/mL | Geometric Coefficient of Variation 18.7 |
| Hepatic Impairment: Child-Pugh A | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 21.9 ng*hr/mL | Geometric Coefficient of Variation 28 |
| Hepatic Impairment: Child-Pugh B | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (5,4,5,3,6) | 18.9 ng*hr/mL | Geometric Coefficient of Variation 58.4 |
| Hepatic Impairment: Child-Pugh B | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 28.9 ng*hr/mL | Geometric Coefficient of Variation 32.7 |
| Hepatic Impairment: Child-Pugh B | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (3,3,1,3,3) | 17.1 ng*hr/mL | Geometric Coefficient of Variation 77.4 |
| Hepatic Impairment: Child-Pugh B | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 0.274 ng*hr/mL | Geometric Coefficient of Variation 195 |
| Hepatic Impairment: Child-Pugh C | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 21.3 ng*hr/mL | Geometric Coefficient of Variation 38.5 |
| Hepatic Impairment: Child-Pugh C | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (3,3,1,3,3) | 6.67 ng*hr/mL | — |
| Hepatic Impairment: Child-Pugh C | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 1.45 ng*hr/mL | Geometric Coefficient of Variation 57 |
| Hepatic Impairment: Child-Pugh C | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (5,4,5,3,6) | 25.5 ng*hr/mL | Geometric Coefficient of Variation 44.6 |
| HCV Without Hepatic Impairment | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (5,4,5,3,6) | 8.61 ng*hr/mL | Geometric Coefficient of Variation 22.6 |
| HCV Without Hepatic Impairment | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (3,3,1,3,3) | 13.9 ng*hr/mL | Geometric Coefficient of Variation 58.6 |
| HCV Without Hepatic Impairment | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 21.5 ng*hr/mL | Geometric Coefficient of Variation 15 |
| HCV Without Hepatic Impairment | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 0.0851 ng*hr/mL | Geometric Coefficient of Variation 57 |
| No Hepatic Disease or Impairment | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 26.0 ng*hr/mL | Geometric Coefficient of Variation 12.4 |
| No Hepatic Disease or Impairment | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 0.0971 ng*hr/mL | Geometric Coefficient of Variation 53.4 |
| No Hepatic Disease or Impairment | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (3,3,1,3,3) | 16.0 ng*hr/mL | Geometric Coefficient of Variation 23 |
| No Hepatic Disease or Impairment | Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (5,4,5,3,6) | 10.3 ng*hr/mL | Geometric Coefficient of Variation 56 |
Comparison: Buprenorphine90% CI: [79.46, 197.24]
Comparison: Buprenorphine90% CI: [135.33, 360.81]
Comparison: Buprenorphine90% CI: [162.19, 383.14]
Comparison: Buprenorphine90% CI: [56.44, 158.02]
Comparison: Buprenorphine90% CI: [78.86, 222.84]
Comparison: Buprenorphine90% CI: [135.63, 403.68]
Comparison: Buprenorphine90% CI: [155.52, 448.03]
Comparison: Norbuprenorphine90% CI: [78.21, 324.79]
Comparison: Norbuprenorphine90% CI: [52.47, 217.91]
Comparison: Norbuprenorphine90% CI: [42.74, 177.5]
Comparison: Norbuprenorphine90% CI: [89.79, 372.89]
Comparison: Norbuprenorphine90% CI: [60.24, 250.19]
Comparison: Naloxone90% CI: [33.45, 142.82]
Comparison: Naloxone90% CI: [141.59, 562.3]
Comparison: Naloxone90% CI: [724.85, 3094.59]
Comparison: Naloxone90% CI: [40.3, 190.59]
Comparison: Naloxone90% CI: [34.34, 181.12]
Comparison: Naloxone90% CI: [144.65, 716.52]
Comparison: Naloxone90% CI: [744.08, 3924.47]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [60.92, 116.38]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [82.02, 150.17]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [60.03, 111.92]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [59.89, 114.42]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [74.96, 138]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [101.07, 177.82]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [73.93, 132.61]
Primary
Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
AUC0-last was calculated for buprenorphine, norbuprenorphine, naloxone, and naloxone-3-β-D-glucuronide using non-compartmental analysis: AUC0-last = AUC from time 0 to the time of the last measurable plasma concentration, calculated using the linear trapezoidal rule.
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK population included participants without any major protocol deviations who contributed PK samples and had sufficient evaluable data for the calculation of PK parameters. Eight enrolled participants were excluded due to emesis observed within 4 hours postdose, and two due to protocol violations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Hepatic Impairment: Child-Pugh A | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 8.89 ng*hr/mL | Geometric Coefficient of Variation 33.3 |
| Hepatic Impairment: Child-Pugh A | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 12.5 ng*hr/mL | Geometric Coefficient of Variation 119 |
| Hepatic Impairment: Child-Pugh A | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 0.0726 ng*hr/mL | Geometric Coefficient of Variation 41.8 |
| Hepatic Impairment: Child-Pugh A | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 19.3 ng*hr/mL | Geometric Coefficient of Variation 31.9 |
| Hepatic Impairment: Child-Pugh B | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 14.7 ng*hr/mL | Geometric Coefficient of Variation 55 |
| Hepatic Impairment: Child-Pugh B | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 27.9 ng*hr/mL | Geometric Coefficient of Variation 33.6 |
| Hepatic Impairment: Child-Pugh B | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 9.51 ng*hr/mL | Geometric Coefficient of Variation 71.4 |
| Hepatic Impairment: Child-Pugh B | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 0.291 ng*hr/mL | Geometric Coefficient of Variation 195 |
| Hepatic Impairment: Child-Pugh C | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 20.6 ng*hr/mL | Geometric Coefficient of Variation 40.2 |
| Hepatic Impairment: Child-Pugh C | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 2.25 ng*hr/mL | Geometric Coefficient of Variation 118 |
| Hepatic Impairment: Child-Pugh C | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 1.28 ng*hr/mL | Geometric Coefficient of Variation 60.2 |
| Hepatic Impairment: Child-Pugh C | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 25.2 ng*hr/mL | Geometric Coefficient of Variation 53.7 |
| HCV Without Hepatic Impairment | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 7.02 ng*hr/mL | Geometric Coefficient of Variation 36.5 |
| HCV Without Hepatic Impairment | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 9.91 ng*hr/mL | Geometric Coefficient of Variation 43.4 |
| HCV Without Hepatic Impairment | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 19.1 ng*hr/mL | Geometric Coefficient of Variation 21.8 |
| HCV Without Hepatic Impairment | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 0.0968 ng*hr/mL | Geometric Coefficient of Variation 73 |
| No Hepatic Disease or Impairment | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 22.5 ng*hr/mL | Geometric Coefficient of Variation 15.8 |
| No Hepatic Disease or Impairment | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 0.0915 ng*hr/mL | Geometric Coefficient of Variation 50.9 |
| No Hepatic Disease or Impairment | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 15.0 ng*hr/mL | Geometric Coefficient of Variation 51.8 |
| No Hepatic Disease or Impairment | Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 8.95 ng*hr/mL | Geometric Coefficient of Variation 49.4 |
Comparison: Buprenorphine90% CI: [66.05, 149.43]
Comparison: Buprenorphine90% CI: [110.82, 242.34]
Comparison: Buprenorphine90% CI: [187.1, 423.33]
Comparison: Buprenorphine90% CI: [52.14, 117.98]
Comparison: Buprenorphine90% CI: [81.87, 195.97]
Comparison: Buprenorphine90% CI: [137.21, 318.18]
Comparison: Buprenorphine90% CI: [231.92, 555.17]
Comparison: Norbuprenorphine90% CI: [44.03, 138.49]
Comparison: Norbuprenorphine90% CI: [39.26, 142.41]
Comparison: Norbuprenorphine90% CI: [6.35, 20.66]
Comparison: Norbuprenorphine90% CI: [39, 129.49]
Comparison: Norbuprenorphine90% CI: [58.14, 207.75]
Comparison: Norbuprenorphine90% CI: [52.17, 212.24]
Comparison: Norbuprenorphine90% CI: [8.4, 30.94]
Comparison: Naloxone90% CI: [40.03, 157.12]
Comparison: Naloxone90% CI: [164.93, 611.54]
Comparison: Naloxone90% CI: [707.55, 2777.46]
Comparison: Naloxone90% CI: [53.39, 209.59]
Comparison: Naloxone90% CI: [36.09, 155.71]
Comparison: Naloxone90% CI: [148.44, 607.21]
Comparison: Naloxone90% CI: [638.03, 2752.55]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [66.06, 111.61]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [96.27, 159.13]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [70.21, 118.62]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [65.23, 110.2]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [76.52, 134.06]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [111.43, 191.26]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [81.33, 142.47]
Primary
Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK population included participants without any major protocol deviations who contributed PK samples and had sufficient evaluable data for the calculation of PK parameters. Eight enrolled participants were excluded due to emesis observed within 4 hours postdose, and two due to protocol violations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Hepatic Impairment: Child-Pugh A | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 1.10 ng/mL | Geometric Coefficient of Variation 52.2 |
| Hepatic Impairment: Child-Pugh A | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 9.02 ng/mL | Geometric Coefficient of Variation 29.8 |
| Hepatic Impairment: Child-Pugh A | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 0.0287 ng/mL | Geometric Coefficient of Variation 62.7 |
| Hepatic Impairment: Child-Pugh A | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 0.358 ng/mL | Geometric Coefficient of Variation 99 |
| Hepatic Impairment: Child-Pugh B | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 9.03 ng/mL | Geometric Coefficient of Variation 21.8 |
| Hepatic Impairment: Child-Pugh B | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 0.180 ng/mL | Geometric Coefficient of Variation 73.2 |
| Hepatic Impairment: Child-Pugh B | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 1.04 ng/mL | Geometric Coefficient of Variation 46.5 |
| Hepatic Impairment: Child-Pugh B | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 0.0773 ng/mL | Geometric Coefficient of Variation 159 |
| Hepatic Impairment: Child-Pugh C | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 0.128 ng/mL | Geometric Coefficient of Variation 60.6 |
| Hepatic Impairment: Child-Pugh C | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 1.40 ng/mL | Geometric Coefficient of Variation 27.4 |
| Hepatic Impairment: Child-Pugh C | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 6.75 ng/mL | Geometric Coefficient of Variation 40 |
| Hepatic Impairment: Child-Pugh C | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 0.323 ng/mL | Geometric Coefficient of Variation 28.7 |
| HCV Without Hepatic Impairment | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 0.0361 ng/mL | Geometric Coefficient of Variation 83.8 |
| HCV Without Hepatic Impairment | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 0.203 ng/mL | Geometric Coefficient of Variation 61 |
| HCV Without Hepatic Impairment | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 0.933 ng/mL | Geometric Coefficient of Variation 30.5 |
| HCV Without Hepatic Impairment | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 6.80 ng/mL | Geometric Coefficient of Variation 14.7 |
| No Hepatic Disease or Impairment | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 8.12 ng/mL | Geometric Coefficient of Variation 30.5 |
| No Hepatic Disease or Impairment | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 0.913 ng/mL | Geometric Coefficient of Variation 53.2 |
| No Hepatic Disease or Impairment | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 0.265 ng/mL | Geometric Coefficient of Variation 59.8 |
| No Hepatic Disease or Impairment | Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 0.0286 ng/mL | Geometric Coefficient of Variation 68.1 |
Comparison: Buprenorphine90% CI: [83.35, 172.82]
Comparison: Buprenorphine90% CI: [75.85, 153.36]
Comparison: Buprenorphine90% CI: [117.93, 250.15]
Comparison: Buprenorphine90% CI: [77.66, 163.91]
Comparison: Buprenorphine90% CI: [71.43, 158.43]
Comparison: Buprenorphine90% CI: [64.36, 141.99]
Comparison: Buprenorphine90% CI: [103.08, 224.83]
Comparison: Norbuprenorphine90% CI: [75.44, 242.16]
Comparison: Norbuprenorphine90% CI: [38.82, 118.68]
Comparison: Norbuprenorphine90% CI: [27.01, 86.69]
Comparison: Norbuprenorphine90% CI: [42.75, 137.22]
Comparison: Norbuprenorphine90% CI: [94.62, 329.17]
Comparison: Norbuprenorphine90% CI: [48.6, 161.59]
Comparison: Norbuprenorphine90% CI: [33.87, 117.83]
Comparison: Naloxone90% CI: [51.3, 196.53]
Comparison: Naloxone90% CI: [141.86, 513.9]
Comparison: Naloxone90% CI: [577.22, 2211.44]
Comparison: Naloxone90% CI: [64.5, 247.11]
Comparison: Naloxone90% CI: [38.79, 163.06]
Comparison: Naloxone90% CI: [107.07, 427.17]
Comparison: Naloxone90% CI: [436.49, 1834.8]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [85.94, 143.44]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [87.02, 142.16]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [64.32, 107.35]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [64.75, 108.08]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [100.93, 174.53]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [102.12, 173.1]
Comparison: Naloxone-3-β-D-Glucuronide90% CI: [75.54, 130.61]
Primary
Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Calculated as: (AUC0-inf - AUC0-last)/AUC0-inf \* 100 AUC0-inf, apparent body clearance (CL/F), and apparent volume of distribution during terminal phase (Vz/F) would not have been reported if %AUCextrap was \> 20%.
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK population included participants without any major protocol deviations who contributed PK samples and had sufficient evaluable data for the calculation of PK parameters. Eight enrolled participants were excluded due to emesis observed within 4 hours postdose, and two due to protocol violations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Hepatic Impairment: Child-Pugh A | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 17.2 percentage of AUC0-inf | Standard Deviation 10.8 |
| Hepatic Impairment: Child-Pugh A | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 10.2 percentage of AUC0-inf | Standard Deviation 8.67 |
| Hepatic Impairment: Child-Pugh A | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 6.59 percentage of AUC0-inf | Standard Deviation 1.86 |
| Hepatic Impairment: Child-Pugh A | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 4.98 percentage of AUC0-inf | Standard Deviation 1.74 |
| Hepatic Impairment: Child-Pugh B | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 17.1 percentage of AUC0-inf | Standard Deviation 6.68 |
| Hepatic Impairment: Child-Pugh B | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 3.34 percentage of AUC0-inf | Standard Deviation 1.53 |
| Hepatic Impairment: Child-Pugh B | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 24.3 percentage of AUC0-inf | Standard Deviation 12.4 |
| Hepatic Impairment: Child-Pugh B | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 7.48 percentage of AUC0-inf | Standard Deviation 6.18 |
| Hepatic Impairment: Child-Pugh C | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 3.50 percentage of AUC0-inf | Standard Deviation 2.08 |
| Hepatic Impairment: Child-Pugh C | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 36.1 percentage of AUC0-inf | Standard Deviation 18 |
| Hepatic Impairment: Child-Pugh C | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 1.30 percentage of AUC0-inf | Standard Deviation 0.958 |
| Hepatic Impairment: Child-Pugh C | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 14.2 percentage of AUC0-inf | Standard Deviation 3 |
| HCV Without Hepatic Impairment | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 17.6 percentage of AUC0-inf | Standard Deviation 4.96 |
| HCV Without Hepatic Impairment | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 16.5 percentage of AUC0-inf | Standard Deviation 3.85 |
| HCV Without Hepatic Impairment | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 6.04 percentage of AUC0-inf | Standard Deviation 3.6 |
| HCV Without Hepatic Impairment | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 5.16 percentage of AUC0-inf | Standard Deviation 5.01 |
| No Hepatic Disease or Impairment | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 5.13 percentage of AUC0-inf | Standard Deviation 3.55 |
| No Hepatic Disease or Impairment | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 5.31 percentage of AUC0-inf | Standard Deviation 2.51 |
| No Hepatic Disease or Impairment | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 13.1 percentage of AUC0-inf | Standard Deviation 9.24 |
| No Hepatic Disease or Impairment | Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 15.5 percentage of AUC0-inf | Standard Deviation 5 |
Primary
Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Terminal elimination half-life, calculated as ln(2)/λz. The terminal phase elimination half-life was calculated over a period of at least 2 half-lives.
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK population included participants without any major protocol deviations who contributed PK samples and had sufficient evaluable data for the calculation of PK parameters. Eight enrolled participants were excluded due to emesis observed within 4 hours postdose, and two due to protocol violations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Hepatic Impairment: Child-Pugh A | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 31.4 hours | Geometric Coefficient of Variation 46 |
| Hepatic Impairment: Child-Pugh A | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 41.3 hours | Geometric Coefficient of Variation 39.4 |
| Hepatic Impairment: Child-Pugh A | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 2.15 hours | Geometric Coefficient of Variation 23 |
| Hepatic Impairment: Child-Pugh A | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 7.12 hours | Geometric Coefficient of Variation 26 |
| Hepatic Impairment: Child-Pugh B | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 48.7 hours | Geometric Coefficient of Variation 41 |
| Hepatic Impairment: Child-Pugh B | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 5.91 hours | Geometric Coefficient of Variation 32.5 |
| Hepatic Impairment: Child-Pugh B | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 52.9 hours | Geometric Coefficient of Variation 21.5 |
| Hepatic Impairment: Child-Pugh B | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 5.45 hours | Geometric Coefficient of Variation 53.6 |
| Hepatic Impairment: Child-Pugh C | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 4.55 hours | Geometric Coefficient of Variation 40.4 |
| Hepatic Impairment: Child-Pugh C | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 36.7 hours | Geometric Coefficient of Variation 37.4 |
| Hepatic Impairment: Child-Pugh C | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 4.58 hours | Geometric Coefficient of Variation 28.2 |
| Hepatic Impairment: Child-Pugh C | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 56.4 hours | Geometric Coefficient of Variation 29.5 |
| HCV Without Hepatic Impairment | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 35.2 hours | Geometric Coefficient of Variation 32.6 |
| HCV Without Hepatic Impairment | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 51.2 hours | Geometric Coefficient of Variation 7.37 |
| HCV Without Hepatic Impairment | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 10.9 hours | Geometric Coefficient of Variation 41.9 |
| HCV Without Hepatic Impairment | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 1.87 hours | Geometric Coefficient of Variation 35.6 |
| No Hepatic Disease or Impairment | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 7.40 hours | Geometric Coefficient of Variation 69.4 |
| No Hepatic Disease or Impairment | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 2.06 hours | Geometric Coefficient of Variation 35.6 |
| No Hepatic Disease or Impairment | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 41.4 hours | Geometric Coefficient of Variation 36 |
| No Hepatic Disease or Impairment | Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 36.0 hours | Geometric Coefficient of Variation 50.2 |
Primary
Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
For the determination of λz, only those data points judged to describe the terminal log-linear decline resulting in an adjusted coefficient of determination value (R2) \> 0.7 were used in the regression. A minimum of 3 data points were used in calculating λz.
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK population included participants without any major protocol deviations who contributed PK samples and had sufficient evaluable data for the calculation of PK parameters. Eight enrolled participants were excluded due to emesis observed within 4 hours postdose, and two due to protocol violations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Hepatic Impairment: Child-Pugh A | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 0.0221 1/hour | Geometric Coefficient of Variation 46 |
| Hepatic Impairment: Child-Pugh A | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 0.0168 1/hour | Geometric Coefficient of Variation 39.4 |
| Hepatic Impairment: Child-Pugh A | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 0.322 1/hour | Geometric Coefficient of Variation 23 |
| Hepatic Impairment: Child-Pugh A | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 0.0974 1/hour | Geometric Coefficient of Variation 26 |
| Hepatic Impairment: Child-Pugh B | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 0.0142 1/hour | Geometric Coefficient of Variation 41 |
| Hepatic Impairment: Child-Pugh B | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 0.117 1/hour | Geometric Coefficient of Variation 32.5 |
| Hepatic Impairment: Child-Pugh B | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 0.0131 1/hour | Geometric Coefficient of Variation 21.5 |
| Hepatic Impairment: Child-Pugh B | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 0.127 1/hour | Geometric Coefficient of Variation 53.6 |
| Hepatic Impairment: Child-Pugh C | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 0.152 1/hour | Geometric Coefficient of Variation 40.4 |
| Hepatic Impairment: Child-Pugh C | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 0.0189 1/hour | Geometric Coefficient of Variation 37.4 |
| Hepatic Impairment: Child-Pugh C | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 0.151 1/hour | Geometric Coefficient of Variation 28.2 |
| Hepatic Impairment: Child-Pugh C | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 0.0123 1/hour | Geometric Coefficient of Variation 29.5 |
| HCV Without Hepatic Impairment | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 0.0197 1/hour | Geometric Coefficient of Variation 32.6 |
| HCV Without Hepatic Impairment | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 0.0135 1/hour | Geometric Coefficient of Variation 7.37 |
| HCV Without Hepatic Impairment | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 0.0637 1/hour | Geometric Coefficient of Variation 41.9 |
| HCV Without Hepatic Impairment | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 0.371 1/hour | Geometric Coefficient of Variation 35.6 |
| No Hepatic Disease or Impairment | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide (5,7,6,5,4) | 0.0937 1/hour | Geometric Coefficient of Variation 69.4 |
| No Hepatic Disease or Impairment | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone (5,6,5,4,7) | 0.337 1/hour | Geometric Coefficient of Variation 35.6 |
| No Hepatic Disease or Impairment | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine (4,6,5,4,4) | 0.0167 1/hour | Geometric Coefficient of Variation 36 |
| No Hepatic Disease or Impairment | Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine (6,5,5,5,7) | 0.0193 1/hour | Geometric Coefficient of Variation 50.2 |
Primary
Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK population included participants without any major protocol deviations who contributed PK samples and had sufficient evaluable data for the calculation of PK parameters. Eight enrolled participants were excluded due to emesis observed within 4 hours postdose, and two due to protocol violations.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Hepatic Impairment: Child-Pugh A | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 72.0 hours |
| Hepatic Impairment: Child-Pugh A | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 24.0 hours |
| Hepatic Impairment: Child-Pugh A | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 10.0 hours |
| Hepatic Impairment: Child-Pugh A | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 144 hours |
| Hepatic Impairment: Child-Pugh B | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 24.1 hours |
| Hepatic Impairment: Child-Pugh B | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 120 hours |
| Hepatic Impairment: Child-Pugh B | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 120 hours |
| Hepatic Impairment: Child-Pugh B | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 24.0 hours |
| Hepatic Impairment: Child-Pugh C | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 24.0 hours |
| Hepatic Impairment: Child-Pugh C | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 168 hours |
| Hepatic Impairment: Child-Pugh C | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 24.0 hours |
| Hepatic Impairment: Child-Pugh C | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 48.0 hours |
| HCV Without Hepatic Impairment | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 10.0 hours |
| HCV Without Hepatic Impairment | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 144 hours |
| HCV Without Hepatic Impairment | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 71.5 hours |
| HCV Without Hepatic Impairment | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 36.0 hours |
| No Hepatic Disease or Impairment | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 36.0 hours |
| No Hepatic Disease or Impairment | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 96.0 hours |
| No Hepatic Disease or Impairment | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 156 hours |
| No Hepatic Disease or Impairment | Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 10.0 hours |
Primary
Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK population included participants without any major protocol deviations who contributed PK samples and had sufficient evaluable data for the calculation of PK parameters. Eight enrolled participants were excluded due to emesis observed within 4 hours postdose, and two due to protocol violations.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Hepatic Impairment: Child-Pugh A | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 1.25 hours |
| Hepatic Impairment: Child-Pugh A | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 1.25 hours |
| Hepatic Impairment: Child-Pugh A | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 0.875 hours |
| Hepatic Impairment: Child-Pugh A | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 0.500 hours |
| Hepatic Impairment: Child-Pugh B | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 1.50 hours |
| Hepatic Impairment: Child-Pugh B | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 0.750 hours |
| Hepatic Impairment: Child-Pugh B | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 1.25 hours |
| Hepatic Impairment: Child-Pugh B | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 0.750 hours |
| Hepatic Impairment: Child-Pugh C | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 0.500 hours |
| Hepatic Impairment: Child-Pugh C | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 0.875 hours |
| Hepatic Impairment: Child-Pugh C | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 0.750 hours |
| Hepatic Impairment: Child-Pugh C | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 1.00 hours |
| HCV Without Hepatic Impairment | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 1.38 hours |
| HCV Without Hepatic Impairment | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 1.00 hours |
| HCV Without Hepatic Impairment | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 0.750 hours |
| HCV Without Hepatic Impairment | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 1.00 hours |
| No Hepatic Disease or Impairment | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone-3-β-D-Glucuronide | 0.500 hours |
| No Hepatic Disease or Impairment | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Naloxone | 1.13 hours |
| No Hepatic Disease or Impairment | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Norbuprenorphine | 1.00 hours |
| No Hepatic Disease or Impairment | Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide | Buprenorphine | 1.75 hours |