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Effect on Acetaminophen Metabolism by Liquid Formulations

This study has been completed.
Sponsor:
Collaborators:
Harvard University
National Center for Research Resources (NCRR)
Information provided by (Responsible Party):
Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier:
NCT01246713
First received: November 22, 2010
Last updated: March 26, 2013
Last verified: March 2013
History of Changes

November 22, 2010
March 26, 2013
December 2010
May 2011   (final data collection date for primary outcome measure)
Acetaminophen Metabolites [ Time Frame: 8 hours ] [ Designated as safety issue: No ]
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.
Acetaminophen metabolites [ Time Frame: 8 hours ] [ Designated as safety issue: No ]
Blood an urine will be assayed for APAP, APAP glucuronide, APAP sulfate, APAP glutathione, APAP cysteinate and APAP mercapturate
Complete list of historical versions of study NCT01246713 on ClinicalTrials.gov Archive Site
Not Provided
Not Provided
Not Provided
Not Provided
 
Effect on Acetaminophen Metabolism by Liquid Formulations
Effect on Acetaminophen Metabolism by Liquid Formulations: Do Excipients in Liquid Formulation Prevent Production of Toxic Metabolites?

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.

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.
Interventional
Not Provided
Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
  • Acetaminophen Metabolism
  • Acetaminophen Poisoning
  • Drug Metabolism by Excipients
  • Drug: Acetaminophen liquid formulation
    Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation.
  • Drug: Acetaminophen solid formulation
    Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation.
  • Placebo Comparator: Acetaminophen solid formulation
    Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation.
    Intervention: Drug: Acetaminophen solid formulation
  • Active Comparator: Acetaminophen liquid formulation
    Subjects in this arm will receive a 15mg/kg dose of a liquid acetaminophen formulation.
    Intervention: Drug: Acetaminophen liquid formulation
Ganetsky M, Böhlke M, Pereira L, Williams D, LeDuc B, Guatam S, Salhanick SD. Effect of excipients on acetaminophen metabolism and its implications for prevention of liver injury. J Clin Pharmacol. 2013 Apr;53(4):413-20. doi: 10.1002/jcph.24. Epub 2013 Feb 22.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
15
July 2012
May 2011   (final data collection date for primary outcome measure)

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
Both
18 Years to 40 Years
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01246713
2010P-000135, UL1RR025758
No
Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center
  • Harvard University
  • National Center for Research Resources (NCRR)
Principal Investigator: Michael Ganetsky, MD Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center
March 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP