A Study of Glyceryl Tri-(4-phenylbutyrate) (GT4P)

A Randomized, Crossover, Open-label Phase 1 Study of Glyceryl Tri-(4-phenylbutyrate) (GT4P)

To determine the safety and tolerability of single oral doses of HPN-100 as a formulation (GT4P-F) and GT4P as the active pharmaceutical ingredient (GT4P-API) administered to healthy male subjects.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: HPN-100; Drug: Ammonul; Drug: Buphenyl

Detailed Description

A randomized, open-label, four-treatment, four-period crossover study in which healthy male subjects received a single dose of each of the following four treatments on four separate dosing days, 7 days apart:

• Oral sodium phenylbutyrate (Buphenyl®) equivalent to 3 g/m2 of 4-phenylbutyric acid (PBA) per dose
• Oral GT4P-F mole equivalents to 3 g/m2 of PBA per dose
• Oral GT4P-API mole equivalents to 3 g/m2 of PBA per dose
• Intravenous 10% sodium phenylacetate plus 10% sodium benzoate (Ammonul®) 2.75 g/m2

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

Contacts and Locations

Study Locations

• Ukraine
  • Kharkiv, Ukraine, 61011
    • Medical Sanitary Division #2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

Subjects were required to fulfill the following criteria in order to participate in the study:

• Males aged 18 to 45 years of age
• Ability to provide written, informed consent before any study-related procedures, and ability, in the opinion of the investigator, to comply with all the requirements of the study
• Subjects who were in good health as determined by a medical history, physical examination, serum chemistry, hematology, urinalysis, 12 lead ECG, and vital signs
• Weight within the range of 60-120 kg

Exclusion Criteria:

Subjects who fulfilled any of the following criteria were excluded from the study:

• Clinically significant history or evidence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, neurologic, immunologic, or psychiatric disorder(s), as determined by the investigator
• Clinically significant abnormal laboratory values (as determined by the investigator)
• Significant illness within 14 days prior to screening
• Any disorder that might significantly interfere with the absorption, distribution, metabolism, or excretion of any drug
• Use of any prescription medication within 14 days prior to screening
• Use of dietary supplements, herbal medicines, vitamins, or over-the-counter medication(s) (with the exception of acetaminophen ≤ 500 mg/day) within 10 days prior to first dosing
• Positive drugs of abuse urine test at screening or pre-dose day (cocaine, amphetamines, barbiturates, opiates, benzodiazepines, cannabinoids, methadone)
• Positive alcohol breath test at screening or pre-dose day
• Donation or loss of blood (500 ml or more) within 30 days prior to first dosing, or during the study
• Donation or loss of plasma within 7 days prior to first dosing, or during the study
• History of or current hepatitis or carriers of hepatitis B surface antigen (HBsAg) and/or hepatitis C antibodies (anti-HC)
• History of acquired immunodeficiency syndrome (AIDS) or determined HIV positive at screening
• Use of any investigational drug within 12 weeks prior to first dosing
• Known hypersensitivity to sodium phenylbutyrate or similar drugs
• Previous exposure to sodium phenylbutyrate

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GT4P-F; GT4P-F (80% GT4P) was supplied as an odorless, colorless, tasteless liquid oil in 125 ml bottles. This formulation was designed to be mixed in water and create a self-emulsifying suspension, thus administered in water for the trial. The administered dose was calculated to contain the number of moles of PBA equivalent to 3 g/m2 of PBA. GT4P-F was mixed in 50 ml of water, taken orally, and then the cup rinsed with 50 ml of water and taken orally. GT4P-F was stored at ambient temperature away from light.	Drug: HPN-100; HPN-100 is a triglyceride that has a similar mechanism of action as Buphenyl. It is a liquid with minimal taste and odor. HPN-100 is broken down to phenylbutyric acid (PBA). PBA is converted to phenyl acetic acid (PAA) that is the active metabolite. Three teaspoons of HPN-100 (~17.4mL) delivers equivalent amount of PBA that 40 tablets of NaPBA do.
Experimental: GT4P-API; GT4P-API was supplied as an odorless, colorless, tasteless oil in 125 ml bottles. The administered dose was calculated to contain the number of moles of PBA equivalent to 3 g/m2 of PBA. GT4P-API was taken orally and washed down with 100 ml of water. GT4P-API was stored at ambient temperature, away from light.	Drug: HPN-100; HPN-100 is a triglyceride that has a similar mechanism of action as Buphenyl. It is a liquid with minimal taste and odor. HPN-100 is broken down to phenylbutyric acid (PBA). PBA is converted to phenyl acetic acid (PAA) that is the active metabolite. Three teaspoons of HPN-100 (~17.4mL) delivers equivalent amount of PBA that 40 tablets of NaPBA do.
Active Comparator: Ammonul; Ammonul® was supplied as single-use glass vials of 10% sodium phenylacetate and 10% sodium benzoate for intravenous injection. Ammonul® was diluted before use with sterile dextrose injection 10% to a concentration of 9 mg/ml. Once diluted it was kept at room temperature and used within 24 hours. The dose was 2.75 g/m2 and was administered as an intravenous infusion over a 120-minute period. Ammonul® was stored at 25°C, within a range of 15-30°C.	Drug: Ammonul
Active Comparator: Buphenyl; Sodium phenylbutyrate or Buphenyl® was supplied as a white powder in 250 g bottles. The required amount of powder (equivalent to 3 g/m2 of PBA) was weighed out, mixed in 100 ml of water, and administered orally. Doses were calculated on a weight/volume basis and corrected for sodium content and purity. Buphenyl® was stored at ambient temperature.	Drug: Buphenyl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The rate of adverse events	33 Days

Collaborators and Investigators

• Sponsor: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Collaborators: Ucyclyd Pharma, Inc.
• Investigators: Principal Investigator: Igor Zupanets, MD, The National University of Pharmacy

Publications and helpful links

General Publications

• McGuire BM, Zupanets IA, Lowe ME, Xiao X, Syplyviy VA, Monteleone J, Gargosky S, Dickinson K, Martinez A, Mokhtarani M, Scharschmidt BF. Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis. Hepatology. 2010 Jun;51(6):2077-85. doi: 10.1002/hep.23589.

Study record dates

Study Major Dates

• Study Start: March 1, 2005
• Study Completion (Actual): July 1, 2005

Study Registration Dates

• First Submitted: September 15, 2009
• First Submitted That Met QC Criteria: September 15, 2009
• First Posted (Estimate): September 16, 2009

Study Record Updates

• Last Update Posted (Estimate): January 16, 2017
• Last Update Submitted That Met QC Criteria: January 13, 2017
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Healthy Volunteers; sodium phenylbutyrate; Buphenyl; GT4P; HPN-100; Glyceryl tri-(4-phenylbutyrate); Ammonul; Sodium phenylacetate; sodium benzoate
• Additional Relevant MeSH Terms: Antineoplastic Agents; 4-phenylbutyric acid
• Other Study ID Numbers: UP 1204-001