Effect on Acetaminophen Metabolism by Liquid Formulations

Study Overview
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Brief Summary
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The purpose of this study is to determine whether excipients in the liquid formulation of acetaminophen prevent the formation of the toxic metabolites of acetaminophen.

Detailed Description
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Acetaminophen (APAP) poisoning is the most frequent cause of acute hepatic failure in the United States. Toxicity requires cytochrome P-450 bioactivation of APAP. Children are less susceptible to APAP toxicity; the current theory is that they have different metabolism than adults. However, children's liquid preparations of APAP contain excipients which have been shown to inhibit APAP bioactivation in vitro and in rodents. Children tend to ingest liquid preparations, which could potentially explain their decreased susceptibility instead of an intrinsically different metabolism. Further, our review of Poison Center epidemiologic data shows that liquid preparations are less toxic in adults. Our hypothesis is that excipients in liquid preparations inhibit the bioactivation of APAP. The design is a pharmacokinetic cross-over study in humans. Healthy adult subjects will be recruited for administration of therapeutic doses of APAP in capsule and liquid formulations. Plasma via a heplock will be collected at serial time points up to 8 hours and assayed for APAP and its metabolites. After a washout period, subjects will receive the same dose of APAP in the alternate preparation. The pattern of metabolites, indicating the activity of the bioactivating enzymes, will be compared. A significant difference in P-450 metabolites will support the hypothesis and provide preliminary data for studies in patients who have ingested potentially toxic doses of APAP. Ultimately, this work could support development of novel antidotal therapy for APAP overdose.

Official Title
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Effect on Acetaminophen Metabolism by Liquid Formulations: Do Excipients in Liquid Formulation Prevent Production of Toxic Metabolites?

Conditions
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Acetaminophen Metabolism, Acetaminophen Poisoning, Drug Metabolism by Excipients

Intervention / Treatment
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* Drug: Acetaminophen liquid formulation
* Drug: Acetaminophen solid formulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteer ages 18-40 Not taking any chronic medications Exclusion Criteria: Pregnancy Any history of liver disease Frequent alcohol use (2 or more drinks more than 4 times per week) Unable to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Acetaminophen solid formulation<br>Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation. | Drug: Acetaminophen solid formulation<br>* Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation.<br>|
| Active Comparator: Acetaminophen liquid formulation<br>Subjects in this arm will receive a 15mg/kg dose of a liquid acetaminophen formulation. | Drug: Acetaminophen liquid formulation<br>* Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acetaminophen Metabolites | Area-under-curve from time zero to 8 hours for APAP-cysteinate metabolite. Serum was collected just prior to and at hours 1, 2, 4, 6, and 8 after administration of the APAP dose. | 8 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acetaminophen, excipients