Single-Dose Pharmacokinetics and Safety of Oral Lofexidine in Hepatically-Impaired Subjects

This is a Phase 1, open-label, parallel-group, single-dose study of lofexidine in 6 adult subjects with mild hepatic impairment (Child Pugh score of 5 6), 6 adult subjects with moderate hepatic impairment (Child Pugh score 7 9), 6 adult subjects with severe hepatic impairment (Child Pugh score 10 15), and 6 control subjects with normal hepatic function with mean age, body mass index (BMI), and gender distribution targeted to be similar to the impaired hepatic function cohorts.

Study Overview

• Status: Completed
• Conditions: Liver Failure
• Intervention / Treatment: Drug: Lofexidine Hydrochloride (HCl) tablets

Detailed Description

This is a Phase 1, open-label, parallel-group, single-dose study of lofexidine in 6 adult subjects with mild hepatic impairment (Child Pugh score of 5 6), 6 adult subjects with moderate hepatic impairment (Child Pugh score 7 9), 6 adult subjects with severe hepatic impairment (Child Pugh score 10 15), and 6 control subjects with normal hepatic function with mean age, body mass index (BMI), and gender distribution targeted to be similar to the impaired hepatic function cohorts. Subjects will be confined to an inpatient facility from the evening before dosing to 144 hours after dosing.

Subjects who successfully complete screening will report to the inpatient facility at an appropriate time the evening before study drug administration (Day 1) to ensure a minimum 10 hour fast. The next morning (Day 1) while still fasting, subjects will receive a single, oral dose of 400 µg lofexidine HCl (two 200 µg tablets). Blood samples will be collected for pharmacokinetic (PK) analysis at multiple time points over the next 144 hours (Day 7). Pooled urine samples will be collected at 0 3 hours, 3 6 hours, 6 12 hours, 12 24 hours, 24 48 hours, 48 96 hours, 96 120 hours and 120 144 hours post-dose. Safety will be assessed by recording adverse events (AEs), measuring vital signs (blood pressure and pulse rate) and clinical laboratory tests (chemistry, hematology, and urinalysis), recording 12 lead safety and Holter electrocardiograms (ECGs), and performing physical exams.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Site will evaluate each subject for criteria in detail, which will include:

1. Between ages of 18 to 65 years at enrollment with a BMI between 19 and 38 kg/m2, inclusive.

2. Subject is eligible to enter the study if:

   • Matched control subject: normal hepatic function and free from other clinically significant illnesses or disease, and medical history, physical examination, laboratory results, and other tests consistent with health, as determined by the Investigator.
   • Subject with mild hepatic impairment: Child-Pugh hepatic dysfunction staging system score of 5-6 Points (Stage A) and medical history, physical examination, laboratory results, and other tests consistent with their hepatic impairment, as determined by the Investigator.
   • Subject with moderate hepatic impairment: Child-Pugh hepatic dysfunction staging system score of 7 9 Points (Stage B) and medical history, physical examination, laboratory results, and other tests consistent with their hepatic impairment, as determined by the Investigator.
   • Subject with severe hepatic impairment: Child-Pugh hepatic dysfunction staging system score of 10-15 Points (Stage C) and medical history, physical examination, laboratory results, and other tests consistent with their hepatic impairment, as determined by the Investigator.

Exclusion Criteria:

Site will evaluate each subject for criteria in detail, which will include:

1. The matched control subject has a history of clinically significant disease, including cardiovascular, gastrointestinal (GI), renal, hepatic, pulmonary, endocrine, hematologic, vascular, immunologic, metabolic, or collagen disease or the hepatically-impaired subject has a history of clinically significant disease including cardiovascular, GI, renal, pulmonary, endocrine, hematologic, vascular, immunologic, metabolic, or collagen disease.

2. Abnormal cardiovascular exam at Screening, including any of the following:

   • clinically significant abnormal ECG (e.g., second or third degree heart block, uncontrolled arrhythmia, QTcF (Fridericia's correction) interval >450 msec for males and >470 msec for females).
   • heart rate <45 bpm or symptomatic bradycardia;
   • systolic blood pressure <90 mmHg or symptomatic hypotension;
   • blood pressure >160/100 mmHg; or
   • prior history of myocardial infarction.

3. Subjects with hepatic impairment will not be eligible to participate in the study if any of the following exclusion criteria also apply:

   • Significant bleeding diathesis or esophageal bleeding within the last 8 weeks.
   • Evidence of hepatic function deterioration within the last 4 weeks as indicated by liver transaminases, alkaline phosphatase, and gamma-glutamyl transpeptidase or a ≥50% worsening of serum bilirubin or prothrombin time.
   • History of surgical portosystemic shunt.
   • Prothrombin time >18 seconds.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Normal Hepatic function	Drug: Lofexidine Hydrochloride (HCl) tablets; Lofexidine HCl tablets (two 200 µg tablets) will be administered orally with 240 mL room temperature tap water as a single 400 µg dose in the morning on Day 1 after a 10 hour overnight fast.
Active Comparator: Mild Hepatic Impairment; (Child-Pugh score 5-6)	Drug: Lofexidine Hydrochloride (HCl) tablets; Lofexidine HCl tablets (two 200 µg tablets) will be administered orally with 240 mL room temperature tap water as a single 400 µg dose in the morning on Day 1 after a 10 hour overnight fast.
Active Comparator: Moderate Hepatic Impairment; (Child-Pugh score 7-9)	Drug: Lofexidine Hydrochloride (HCl) tablets; Lofexidine HCl tablets (two 200 µg tablets) will be administered orally with 240 mL room temperature tap water as a single 400 µg dose in the morning on Day 1 after a 10 hour overnight fast.
Active Comparator: Severe Hepatic Impairment; (Child-Pugh score 10-15)	Drug: Lofexidine Hydrochloride (HCl) tablets; Lofexidine HCl tablets (two 200 µg tablets) will be administered orally with 240 mL room temperature tap water as a single 400 µg dose in the morning on Day 1 after a 10 hour overnight fast.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK Profile: Cmax, Tmax, AUC, λz, CL/F, T½, CLr, CLd, Ae	Cmax, Tmax, AUC, λz, CL/F, T½, CLr, CLd, Ae	pre dose until 144 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events		screening through day 7
Clinical laboratory tests	hematology, chemistry, urinalysis	screening through day 7
Vital signs	blood pressure and pulse	screening through day 7
12-lead ECG		screening through day 7
Holter ECG		pre dose through 8 hours post dose

Collaborators and Investigators

• Sponsor: USWM, LLC (dba US WorldMeds)
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Study Director: James Longstreth, PhD, USWM, LLC (dba US WorldMeds); Study Director: Charles Gorodetzky, MD, PhD, USWM, LLC (dba US WorldMeds)

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: July 29, 2014
• First Submitted That Met QC Criteria: December 16, 2014
• First Posted (Estimate): December 17, 2014

Study Record Updates

• Last Update Posted (Actual): February 23, 2018
• Last Update Submitted That Met QC Criteria: February 22, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: hepatic, hepatic impairment, lofexidine
• Additional Relevant MeSH Terms: Digestive System Diseases; Hepatic Insufficiency; Liver Diseases; Liver Failure; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Peripheral Nervous System Agents; Sensory System Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Narcotic Antagonists; Lofexidine
• Other Study ID Numbers: USWM-LX1-1007; 1R01DA030916 (Other Grant/Funding Number: National Institute on Drug Abuse)