Pathogenesis of Adverse Drug Reactions

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Seizures

Intervention / Treatment
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* Other: No intervention; Urine Collection


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients receiving Carbamazepine or Valproic Acid<br> | Other: No intervention; Urine Collection<br>* Urine collected from children receiving carbamazepine or valproic acid as part of their clinical management<br>* Other names: valproic acid: Depakote;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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seizures, Epilepsy