Single Dose Pharmacokinetics of Suboxone Study in Hepatic Impaired Subjects

NCT01846455 | Completed Phase 4 Results

• 1 other identifier: RB-US-08-0003
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 3

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.

Conditions

Hepatic Failure; Hepatic Impairment; Chronic Hepatitis C Infection With Hepatic Coma

Keywords

Hepatic; Hepatitis C Virus; Suboxone; Buprenorphine; Naloxone

Outcome Measures

Primary Outcomes (10)

• 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.

  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

• 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

  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.

  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 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

  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%.

  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 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.

  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 (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.

  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 (CL/F) of Buprenorphine and Naloxone

  Apparent body clearance (only for buprenorphine and naloxone), calculated as Dose/AUC0-inf.

  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 (Vz/F) of Buprenorphine and Naloxone

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

  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

Study Arms (5)

Hepatic Impairment: Child-Pugh A

EXPERIMENTAL

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; Drug: Promethazine

Hepatic Impairment: Child-Pugh B

EXPERIMENTAL

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; Drug: Promethazine

Hepatic Impairment: Child-Pugh C

EXPERIMENTAL

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; Drug: Promethazine

HCV Without Hepatic Impairment

EXPERIMENTAL

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; Drug: Promethazine

No Hepatic Disease or Impairment

ACTIVE COMPARATOR

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; Drug: Promethazine

Interventions

2.0mg Buprenorphine/0.5mg Naloxone DRUG

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.

Also known as: Suboxone®

HCV Without Hepatic Impairment; Hepatic Impairment: Child-Pugh A; Hepatic Impairment: Child-Pugh B; Hepatic Impairment: Child-Pugh C; No Hepatic Disease or Impairment

Promethazine DRUG

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.

HCV Without Hepatic Impairment; Hepatic Impairment: Child-Pugh A; Hepatic Impairment: Child-Pugh B; Hepatic Impairment: Child-Pugh C; No Hepatic Disease or Impairment

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Indivior Inc.: lead

Study Sites (3)

Clinical Pharmacology of Miami, Inc.

Hialeah, Florida, 33014-3616, United States

Location

Orlando Clinical Research Center

Orlando, Florida, 32809, United States

Location

American Research Corporation (ARC)

San Antonio, Texas, 78215, United States

Location

Related Publications (1)

• Nasser AF, Heidbreder C, Liu Y, Fudala PJ. Pharmacokinetics of Sublingual Buprenorphine and Naloxone in Subjects with Mild to Severe Hepatic Impairment (Child-Pugh Classes A, B, and C), in Hepatitis C Virus-Seropositive Subjects, and in Healthy Volunteers. Clin Pharmacokinet. 2015 Aug;54(8):837-49. doi: 10.1007/s40262-015-0238-6.

  PMID: 25603822 RESULT

MeSH Terms

Conditions

Liver Failure; Hepatitis C

Interventions

Buprenorphine, Naloxone Drug Combination; Promethazine

Condition Hierarchy (Ancestors)

Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis

Intervention Hierarchy (Ancestors)

Buprenorphine; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Naloxone; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations; Propylamines; Amines; Organic Chemicals; Phenothiazines; Sulfur Compounds; Heterocyclic Compounds, 3-Ring

Results Point of Contact

• Title: Reckitt Benckiser Pharmaceuticals, Inc.
• Organization: RECKITT BENCKISER PHARMACEUTICALS, INC.

804-379-1090

Study Officials

• 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)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 1, 2013
• First Posted: May 3, 2013
• Study Start: September 1, 2012
• Primary Completion: April 1, 2013
• Study Completion: May 1, 2013
• Last Updated: October 24, 2016
• Results First Posted: October 24, 2016

Record last verified: 2016-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)