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Single Dose Pharmacokinetics of Suboxone Study in Hepatic Impaired Subjects

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Indivior Inc.
ClinicalTrials.gov Identifier:
NCT01846455
First received: May 1, 2013
Last updated: September 9, 2016
Last verified: September 2016
  Purpose
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.

Condition Intervention Phase
Hepatic Failure Hepatic Impairment Chronic Hepatitis C Infection With Hepatic Coma Drug: 2.0mg Buprenorphine/0.5mg Naloxone Drug: Promethazine Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pharmacokinetics of Buprenorphine and Naloxone in Subjects With Mild to Severe Hepatic Impairment (Child-Pugh Classes, A, B, and C), in HCV-Seropositive Subjects, and in Healthy Volunteers

Resource links provided by NLM:


Further study details as provided by Indivior Inc.:

Primary Outcome Measures:
  • 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 [ 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 ]

    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 [ 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 ]
  • Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) 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 ]

    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 [ 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 ]
  • 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 ]
  • 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 [ 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 ]

    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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    Apparent volume of distribution during terminal phase (only for buprenorphine and naloxone), calculated as Dose/(λz • AUC0-inf).


Enrollment: 43
Study Start Date: September 2012
Study Completion Date: May 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: 2.0mg 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.
Other Name: Suboxone®
Drug: Promethazine
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.
Experimental: 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.
Drug: 2.0mg 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.
Other Name: Suboxone®
Drug: Promethazine
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.
Experimental: 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.
Drug: 2.0mg 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.
Other Name: Suboxone®
Drug: Promethazine
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.
Experimental: 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.
Drug: 2.0mg 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.
Other Name: Suboxone®
Drug: Promethazine
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.
Active Comparator: 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.
Drug: 2.0mg 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.
Other Name: Suboxone®
Drug: Promethazine
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.

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
  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01846455

Locations
United States, Florida
Clinical Pharmacology of Miami, Inc.
Hialeah, Florida, United States, 33014-3616
Orlando Clinical Research Center
Orlando, Florida, United States, 32809
United States, Texas
American Research Corporation (ARC)
San Antonio, Texas, United States, 78215
Sponsors and Collaborators
Indivior Inc.
Investigators
Principal Investigator: Thomas Lasseter, MD Clinical Pharmacology of Miami, Inc.
Principal Investigator: Thomas Marabury, MD Orlando Clinical Research Center
Principal Investigator: Eric J. Lawitz, MD American Research Corporation (ARC)
  More Information

Publications:
Responsible Party: Indivior Inc.
ClinicalTrials.gov Identifier: NCT01846455     History of Changes
Other Study ID Numbers: RB-US-08-0003
Study First Received: May 1, 2013
Results First Received: August 7, 2015
Last Updated: September 9, 2016
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by Indivior Inc.:
Hepatic
Hepatitis C Virus
Suboxone
Buprenorphine
Naloxone

Additional relevant MeSH terms:
Hepatitis
Hepatitis C
Hepatitis, Chronic
Hepatitis C, Chronic
Liver Diseases
Liver Failure
Hepatic Encephalopathy
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Flaviviridae Infections
RNA Virus Infections
Hepatic Insufficiency
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Metabolic Diseases
Naloxone
Buprenorphine
Buprenorphine, Naloxone Drug Combination
Diphenhydramine
Promethazine
Narcotic Antagonists
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Antipruritics
Dermatologic Agents
Histamine H1 Antagonists

ClinicalTrials.gov processed this record on June 23, 2017