Clinical trial NCT01246713: Effect on Acetaminophen Metabolism by Liquid Formulations
Official title: Effect on Acetaminophen Metabolism by Liquid Formulations: Do Excipients in Liquid Formulation Prevent Production of Toxic Metabolites?
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Acetaminophen Metabolism
Acetaminophen Poisoning
Drug Metabolism by Excipients
Keywords: acetaminophen
excipients
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: Harvard University
name: National Center for Research Resources (NCRR)
First posted: 2010-11-23
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Acetaminophen Metabolites
timeFrame: 8 hours
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Harvard - Thorndike Clinical Research Center at Beth Israel Deaconess Medical Center
state: Massachusetts
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Michael Ganetsky, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.