Single Dose Pharmacokinetics of Suboxone Study in Hepatic Impaired Subjects

Condition(s) targeted: Hepatic Failure; Hepatic Impairment; Chronic Hepatitis C Infection With Hepatic Coma

Intervention: 2.0mg Buprenorphine/0.5mg Naloxone (Drug); Promethazine (Drug)

Phase: Phase 4

Status: Completed

Sponsored by: Reckitt Benckiser Pharmaceuticals Inc.

Official(s) and/or principal investigator(s):
Thomas Lasseter, MD, Principal Investigator, Affiliation: Clinical Pharmacology of Miami, Inc.
Thomas Marabury, MD, Principal Investigator, Affiliation: Orlando Clinical Research Center
Eric J. Lawitz, MD, Principal Investigator, Affiliation: American Research Corporation (ARC)

Pharmacokinetics of Buprenorphine and Naloxone in Subjects with Mild to Severe Hepatic Impairment and in HCV-Seropositive Subjects, and in Healthy Volunteers.

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

Study design: Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of buprenorphine, norbuprenorphine and naloxone

Maximum Observed Plasma Concentration (CMAX) of buprenorphine, norbuprenorphine and naloxone

Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf) of buprenorphine, norbuprenorphine and naloxone

Time to reach the maximum plasma concentration (tmax) of buprenorphine, norbuprenorphine and naloxone

Terminal elimination rate-constant (λz) of buprenorphine, norbuprenorphine and naloxone

Terminal elimination half-life (t1/2) of buprenorphine, norbuprenorphine and naloxone

Apparent body clearance (CL/F) of buprenorphine

Apparent volume of distribution (Vdz/F) of buprenorphine

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

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

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

Clinical Pharmacology of Miami, Inc., Hialeah, Florida 33014-3616, United States

Orlando Clinical Research Center, Orlando, Florida 32809, United States

American Research Corporation (ARC), San Antonio, Texas 78215, United States

Starting date: August 2012
Last updated: August 20, 2013