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.

Study Overview

• Status: Completed
• Conditions: Acetaminophen Poisoning; Acetaminophen Metabolism; Drug Metabolism by Excipients
• Intervention / Treatment: Drug: Acetaminophen solid formulation; Drug: Acetaminophen liquid formulation

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Harvard - Thorndike Clinical Research Center at Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: National Center for Research Resources (NCRR); Harvard University
• Investigators: Principal Investigator: Michael Ganetsky, MD, Beth Israel Deaconess Medical Center

Publications and helpful links

General Publications

• Ganetsky M, Bohlke 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: November 22, 2010
• First Submitted That Met QC Criteria: November 22, 2010
• First Posted (Estimate): November 23, 2010

Study Record Updates

• Last Update Posted (Actual): May 8, 2017
• Last Update Submitted That Met QC Criteria: March 28, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: acetaminophen; excipients
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Poisoning; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: 2010P000135; UL1RR025758 (U.S. NIH Grant/Contract)