Protective Effects of Propylene Glycol in Daily Acetaminophen Dosing

Acetaminophen Toxicity Clinical Trial

— APAPII  

Official title:

Protective Effects of Propylene Glycol in Daily Acetaminophen Dosing

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02322879
• Other study ID #: 2013P-000070
• Status: Active, not recruiting
• Phase: Phase 4
• First received: October 22, 2014
• Last updated: September 8, 2015
• Start date: May 2013
• Est. completion date: December 2017

Study information

• Verified date: September 2015
• Source: Beth Israel Deaconess Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

A purpose of this protocol is to is to compare the metabolites of the toxic bioactivating pathway after acetaminophen alone or acetaminophen followed by Propylene Glycol (PG) and to determine if it prevents the formation of the toxic metabolites of acetaminophen.

Description:

The purpose of this protocol is to contribute to our overarching purpose, which is to determine if inhibiting the bioactivation of acetaminophen (APAP) can prevent liver injury, and to further describe the initiating mechanisms of APAP induced liver injury. APAP induced liver injury is caused by metabolism and/or the resulting metabolites when APAP undergoes reductive metabolism via the cytochrome P450 (CYP) system, principally via CYP 2E1. Inhibition of CYP 2E1 activity protects against toxicity in rodents and tissue culture 1, 2. Our prior research indicates that inhibition of CYP 2E1 by administering a pediatric preparation of APAP containing Propylene Glycol (PG), a known CYP 2E1 inhibitor, results in reduced production of CYP 2E1 derived metabolites via competitive inhibition.

In this proposed protocol the investigators will provide therapeutic doses of APAP and a separately administered non toxic dose of PG over a two-week period to healthy subjects. 20-75% of healthy people who take therapeutic doses of APAP for 7-28 days will have an asymptomatic and subclinical rise in transaminase levels that will return to baseline without adverse effect or therapy. 3 The return to baseline occurs despite continued dosing of APAP (heard review 9 and 17).

A primary purpose is to determine if PG is, in fact, the substance in the liquid preparation responsible for the effect the investigators observed in the investigators initial study. A secondary purpose is to obtain plasma samples for secondary metabolomic analysis to elucidate the effect of CYP 2E1 inhibition.

Specific Aims

• 1 To demonstrate that co-administration of PG with APAP prevents the rise in AST/ALT expected in approximately one third of subjects following therapeutic dosing of APAP over days.

• 2 To show that PG administered with APAP reduces toxic P450-derived metabolite production following therapeutic APAP administration.

• 3 To obtain plasma samples to undergo metabolomic and other analyses to determine the effects of CYP 2E1 inhibition in the setting of APAP administration.

• 4:To undergo metabolomic analyses on the day LFT's peak to determine differences in metabolomics parameters between subjects receiving propylene glycol plus acetaminophen versus just acetaminophen alone.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 50
• Est. completion date: December 2017
• Est. primary completion date: December 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 20 Years to 40 Years

Eligibility

Inclusion Criteria:

• Healthy volunteers ages 20-40

• Patients not taking any chronic medications

Exclusion Criteria:

• Any history of liver disease

• Frequent alcohol use (2 or more drinks more than 4 times per week)

• Pregnant women

• Chronic medical condition requiring daily pharmacotherapy or the use of any daily prescription medications.

• Unable to provide informed consent

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Acetaminophen Toxicity

Intervention

Drug:
• Acetaminophen
Daily administration of 4 grams of acetaminophen.
• Acetaminophen/Propelyne Glycol
Daily administration of 4 grams of acetaminophen and 70 mg/kg propylene glycol.

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Beth Israel Deaconess Medical Center	Harvard University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Inhibition of rise in plasma transaminases		10-14 days after initiation of interventions	No