Protective Effects of Propylene Glycol in Daily Acetaminophen Dosing

Study Overview
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Brief Summary
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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
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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.

Official Title
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Protective Effects of Propylene Glycol in Daily Acetaminophen Dosing

Conditions
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Acetaminophen Toxicity

Intervention / Treatment
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* Drug: First Treatment Period
* Other: Washout
* Drug: Second Treatment Period


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Eligible subjects will then be randomized at a 1:1 ratio to receive either acetaminophen (APAP) or APAP + propylene glycol for 2 weeks (Treatment Period 1). At the end of the Treatment Period 1 subjects will enter the Wash-Out period for 2 weeks. Study subjects will then receive the alternative treatment for 2 weeks (Treatment Period 2). Overall, the maximum duration of treatment is approximately 6 weeks. RESPONDERS: Subjects whose transaminase levels rise to 3 times normal or greater during either of the Treatment Periods will be deemed responders and the intervention will cease. If subjects are in the Treatment Period 1, they will enter the washout period and continue to return daily to ensure that liver function tests decline. After the 2 week washout-period, responders will cross over to Treatment Period 2. If subjects are in the Treatment Period 2 phase, they will continue to return to the CRC and have their transaminases checked until they return to normal.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acetaminophen first, then Acetaminophen + Propylene Glycol<br>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. | Drug: First Treatment Period<br>* (duration: 14 days) Subjects will be randomized to receive either of the 2 interventions (4 grams of solid acetaminophen formulation for two weeks vs. 4 grams of solid acetaminophen formulation + 70 mg/kg/day of liquid propylene glycol)<br>Other: Washout<br>* (duration: 14 days) At the end of the First intervention period all participants will enter a washout period.<br>Drug: Second Treatment Period<br>* (duration: 14 days) At the end of the washout period, participants will receive the alternative intervention.<br>|
| Experimental: Acetaminophen + Propylene Glycol first, then Acetaminophen<br>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. | Drug: First Treatment Period<br>* (duration: 14 days) Subjects will be randomized to receive either of the 2 interventions (4 grams of solid acetaminophen formulation for two weeks vs. 4 grams of solid acetaminophen formulation + 70 mg/kg/day of liquid propylene glycol)<br>Other: Washout<br>* (duration: 14 days) At the end of the First intervention period all participants will enter a washout period.<br>Drug: Second Treatment Period<br>* (duration: 14 days) At the end of the washout period, participants will receive the alternative intervention.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rise in Plasma Transaminases: Proportion of Responders. | 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) | Daily during the treatment periods (D1-D14 and D29 to 42) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acetaminophen, Propylene glycol