Protective Effects of Propylene Glycol in Daily Acetaminophen Dosing

Phase 4

Completed

Conditions: Acetaminophen Toxicity

Interventions: Drug: First Treatment Period
Other: Washout
Drug: Second Treatment Period

Registration Number: NCT02322879

Lead Sponsor: Beth Israel Deaconess Medical Center

Brief 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.

Detailed 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. 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.

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 & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

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

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Acetaminophen first, then Acetaminophen + Propylene Glycol	First Treatment Period	Subjects in this arm will receive 4 grams of solid acetaminophen formulation for two weeks, followed by a two week wash out period. Then, subjects will receive 4 grams of solid acetaminophen formulation in addition to 70 mg/kg/day of liquid propylene glycol for two weeks. The total study time is 6 weeks.
Acetaminophen first, then Acetaminophen + Propylene Glycol	Washout	Subjects in this arm will receive 4 grams of solid acetaminophen formulation for two weeks, followed by a two week wash out period. Then, subjects will receive 4 grams of solid acetaminophen formulation in addition to 70 mg/kg/day of liquid propylene glycol for two weeks. The total study time is 6 weeks.
Acetaminophen first, then Acetaminophen + Propylene Glycol	Second Treatment Period	Subjects in this arm will receive 4 grams of solid acetaminophen formulation for two weeks, followed by a two week wash out period. Then, subjects will receive 4 grams of solid acetaminophen formulation in addition to 70 mg/kg/day of liquid propylene glycol for two weeks. The total study time is 6 weeks.
Acetaminophen + Propylene Glycol first, then Acetaminophen	First Treatment Period	Subjects in this arm will receive 4 grams of solid acetaminophen formulation in addition to 70 mg/kg/day of liquid propylene glycol for two weeks, followed by a two week wash out period. Then, subjects will receive 4 grams of solid acetaminophen formulation for two weeks. The total study time is 6 weeks.
Acetaminophen + Propylene Glycol first, then Acetaminophen	Washout	Subjects in this arm will receive 4 grams of solid acetaminophen formulation in addition to 70 mg/kg/day of liquid propylene glycol for two weeks, followed by a two week wash out period. Then, subjects will receive 4 grams of solid acetaminophen formulation for two weeks. The total study time is 6 weeks.
Acetaminophen + Propylene Glycol first, then Acetaminophen	Second Treatment Period	Subjects in this arm will receive 4 grams of solid acetaminophen formulation in addition to 70 mg/kg/day of liquid propylene glycol for two weeks, followed by a two week wash out period. Then, subjects will receive 4 grams of solid acetaminophen formulation for two weeks. The total study time is 6 weeks.

Primary Outcome Measures

Name	Time	Method
Rise in Plasma Transaminases: Proportion of Responders.	Daily during the treatment periods (D1-D14 and D29 to 42)	Blood tests to monitor Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) were obtained on every visit prior dosing. ALT and AST were analyzed on a Roche Cobas c501 chemistry module at BIDMC. Responders was defined as peak ALT increased 2x baseline (average of first 3 days)

Secondary Outcome Measures