Effect on Acetaminophen Metabolism by Liquid Formulations

Acetaminophen Poisoning Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01246713
• Other study ID #: 2010P-000135
• Secondary ID: UL1RR025758
• Status: Completed
• Phase: N/A
• First received: November 22, 2010
• Last updated: March 26, 2013
• Start date: December 2010
• Est. completion date: July 2012

Study information

• Verified date: March 2013
• Source: Beth Israel Deaconess Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: July 2012
• Est. primary completion date: May 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 40 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Acetaminophen Metabolism
• Acetaminophen Poisoning
• Drug Metabolism by Excipients

Intervention

Drug:
• Acetaminophen liquid formulation
Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation.
• Acetaminophen solid formulation
Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation.

Locations

Country	Name	City	State
United States	Harvard - Thorndike Clinical Research Center at Beth Israel Deaconess Medical Center	Boston	Massachusetts

Sponsors (3)

Lead Sponsor	Collaborator
Beth Israel Deaconess Medical Center	Harvard University, National Center for Research Resources (NCRR)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No