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Completed

NCT Number: NCT01846455

Single Dose Pharmacokinetics of Suboxone Study in Hepatic Impaired Subjects

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.

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Key information

Conditions

Hepatic Failure Blood-Borne Infections Chronic Hepatitis C Infection With Hepatic Coma Communicable Diseases Digestive System Diseases Flaviviridae Infections Hepatic Impairment Hepatic Insufficiency Hepatitis Hepatitis C Hepatitis, Viral, Human Infections Liver Diseases Liver Failure RNA Virus Infections Virus Diseases

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Clinical Pharmacology of Miami, Inc., Hialeah, Florida, United States

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About this study

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

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

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.

Other names: Suboxone®

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.

Primary outcomes

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. 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

  6. 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%.

  7. 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.

  8. 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.

  9. 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.

  10. 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).

Sponsors and collaborators

Lead sponsor

Indivior Inc.

Industry

Registry information

Official study 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

Important dates

Study start
2012
Primary completion
2013
Study completion
2013
First posted
May 3, 2013
Registry last updated
Oct 24, 2016

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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