Protective Effects of Propylene Glycol in Daily Acetaminophen Dosing
Condition: Acetaminophen Toxicity
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): First Treatment Period; Washout; Second Treatment Period
Intervention type(s): Drug; Other; Drug
Intervention description(s): (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); (duration: 14 days) At the end of the First intervention period all participants will enter a washout period.; (duration: 14 days) At the end of the washout period, participants will receive the alternative intervention.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention 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 (Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Acetaminophen; Propylene glycol