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

Amgen

Status and phase: Completed; Phase 1

Conditions: Healthy

Treatments: Drug: Ammonul; Drug: Buphenyl; Drug: HPN-100

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT00977600

UP 1204-001

Details and patient eligibility

About

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.

Full 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 acquired from Horizon in 2024.

Enrollment: 24 patients

Sex: Male

Ages: 18 to 45 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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24 participants in 4 patient groups

GT4P-F

Experimental group

Description:

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.

Treatment:

Drug: HPN-100

GT4P-API

Experimental group

Description:

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.

Treatment:

Drug: HPN-100

Ammonul

Active Comparator group

Description:

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.

Treatment:

Drug: Ammonul

Buphenyl

Active Comparator group

Description:

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.

Treatment:

Drug: Buphenyl