Pathogenesis of Adverse Drug Reactions

August 11, 2017 updated by: Steve Leeder, Children's Mercy Hospital Kansas City

The Role of Drug Metabolizing Enzymes in the Pathogenesis Adverse Drug Reactions in Children

The purpose of the study is to examine the individual metabolic profiles of pediatric patients receiving carbamazepine or valproate therapy, in an attempt to determine identities of the reactive metabolites or, alternatively, the identities of those metabolites that serve as potential precursors to reactive species.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Adverse drug reactions can be broadly defined as any undesirable response associated with therapeutic drug use. A simple and clinically useful classification is to divide adverse events into those that are dose-dependent and largely predictable from the known pharmacologic properties of the compound in question, and those that are dependent on characteristics unique to susceptible individuals, or idiosyncratic in nature.

The long term objective of this research is to characterize the mechanisms responsible for the pathogenesis of idiosyncratic hypersensitivity reactions in children, particularly those involving carbamazepine and other aromatic anticonvulsants.

The study is divided into two phases. Phase 1 of the study involves collecting urine from 50 patients taking CBZ therapeutically. Participants will be asked to provide a spot urine sample during routine health visits. The urine will be analyzed for the presence of CBZ and its metabolites. In Phase 2 of the study, urine will be collected from patients taking either CBZ or VPA therapeutically. If blood samples are drawn from these patients for medical purposes not related to this study the residual blood sample will be recovered before it is discarded for use in genotyping analysis. Participants will be asked to provide a urine sample covering one complete dosing interval of CBZ or VPA (preferably overnight). Patients will also be followed longitudinally, with urine collections at each clinic visit over at least a two year period.

Study Type

Observational

Enrollment (Actual)

274

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Kentucky
      • Louisville, Kentucky, United States, 40202
        • Kosair Children's Hospital
    • Missouri
      • Kansas City, Missouri, United States, 64108
        • Children's Mercy Hospital
    • Utah
      • Salt Lake City, Utah, United States, 84113
        • Primary Children's Hospital, Pediatric Neurology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 16 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Pediatric patients of both genders between 1 and 16 years of age receiving carbamazepine (CBZ) or valproic acid (VPA) as monotherapy or polytherapy

Description

Inclusion Criteria:

  • Pediatric patients of both genders between 1 and 16 years of age receiving CBZ or VPA mono-therapy will be recruited for this study. Additionally, for those patients who are receiving drugs other than CBZ or VPA to control their seizures, if CBZ or VPA are subsequently added to their treatment regimen, then these patients will also be recruited for this study.

Exclusion Criteria:

  • None

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Only
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Patients receiving Carbamazepine or Valproic Acid
Other: No intervention; Urine Collection
Urine collected from children receiving carbamazepine or valproic acid as part of their clinical management
Other Names:
  • carbamazepine: Tegretol
  • valproic acid: Depakote

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine
Time Frame: urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years
1. To examine the individual metabolic profiles of pediatric patients receiving carbamazepine or valproate therapy, in an attempt to determine the identities of the reactive metabolites or, alternatively, the identities of those metabolites that serve as potential precursors to reactive species (e.g., through conjugation with detoxifying compounds such as glutathione).
urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Age-related Changes in Bioactivation
Time Frame: urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years
2. To determine if age-related differences exist regarding the ability of pediatric patients to bioactivate carbamazepine or valproate to reactive metabolites. Data provided below reflect the slope of the least squares regression.
urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Children's Mercy Hospital Kansas City

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Utah
University of Louisville

Investigators

  • Principal Investigator: J. Steven Leeder, Pharm.D., Ph.D.,, Children's Mercy Hospital Kansas City

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2002

Primary Completion (Actual)

March 1, 2010

Study Completion (Actual)

March 1, 2010

Study Registration Dates

First Submitted

September 21, 2005

First Submitted That Met QC Criteria

September 21, 2005

First Posted (Estimate)

September 23, 2005

Study Record Updates

Last Update Posted (Actual)

August 14, 2017

Last Update Submitted That Met QC Criteria

August 11, 2017

Last Verified

August 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PPRU 10606
  • NIH Grant HD044239

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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