Effect on Acetaminophen Metabolism by Liquid Formulations

Beth Israel Lahey Health

Status: Completed

Conditions: Acetaminophen Metabolism; Acetaminophen Poisoning; Drug Metabolism by Excipients

Treatments: Drug: Acetaminophen solid formulation; Drug: Acetaminophen liquid formulation

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT01246713

2010P000135

UL1RR025758 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 15 patients

Sex: All

Ages: 18 to 40 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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15 participants in 2 patient groups, including a placebo group

Acetaminophen solid formulation

Placebo Comparator group

Description:

Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation.

Treatment:

Drug: Acetaminophen solid formulation

Acetaminophen liquid formulation

Active Comparator group

Description:

Subjects in this arm will receive a 15mg/kg dose of a liquid acetaminophen formulation.

Treatment:

Drug: Acetaminophen liquid formulation