Seizures
Conditions
Keywords
seizures, Epilepsy
Brief summary
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
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.
Interventions
OTHERNo intervention; Urine Collection
Urine collected from children receiving carbamazepine or valproic acid as part of their clinical management
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Utah
University of Louisville
Children's Mercy Hospital Kansas City
Study design
Observational model
CASE_ONLY
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
1 Years to 16 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Age-related Changes in Bioactivation | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Carbamazepine Phase 1 No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management | 53 |
| Carbamazepine Phase 2 No intervention; Urine Collection: Urine collected from children receiving carbamazepine as part of their clinical management | 87 |
| Valporic Acid Phase 2 No intervention; Urine Collection: Urine collected from children receiving valproic acid as part of their clinical management | 134 |
| Total | 274 |
Baseline characteristics
| Characteristic | Total | Carbamazepine Phase 2 | Carbamazepine Phase 1 | Valporic Acid Phase 2 |
|---|---|---|---|---|
| Age, Continuous | 10.38 Years STANDARD_DEVIATION 4.16 | 11.0 Years STANDARD_DEVIATION 4 | 9.8 Years STANDARD_DEVIATION 4.6 | 10.2 Years STANDARD_DEVIATION 4.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 6 Participants | 1 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 260 Participants | 81 Participants | 52 Participants | 127 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants | 0 Participants | 4 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 11 Participants | 5 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 238 Participants | 80 Participants | 47 Participants | 111 Participants |
| Sex: Female, Male Female | 117 Participants | 43 Participants | 18 Participants | 56 Participants |
| Sex: Female, Male Male | 157 Participants | 44 Participants | 35 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
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).
Time frame: urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years
Population: Carbamazepine detoxification product (MTHIS) was only measured in the Carbamazepine Phase I and 2 arms. Valproic Acid (NAC) detoxification products were only measured in the Valproic Acid Phase 2 arm. Units of measure for all analytes are nmol per mg creatinine.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Carbamazepine Phase 1 | Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine | 4-Methylthio-2-hydroxyiminostilbene | 15.2 nmol per mg creatinine | Standard Deviation 28.1 |
| Carbamazepine Phase 2 | Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine | 4-Methylthio-2-hydroxyiminostilbene | 13.1 nmol per mg creatinine | Standard Deviation 11.5 |
| Valproic Acid Phase 2 | Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine | 5-N-acetylcysteine-3-ene VPA isomers | 1.15 nmol per mg creatinine | Standard Deviation 1.2 |
| Valproic Acid Phase 2 | Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine | 5-N-acetylcysteine-2-ene VPA | 2.13 nmol per mg creatinine | Standard Deviation 1.68 |
| Valproic Acid Phase 2 | Drug (Valproic Acid or Carbamazepine) Metabolite Profiles in Urine | Total N-acetylcysteine conjugates | 5.88 nmol per mg creatinine | Standard Deviation 5.17 |
Secondary
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.
Time frame: urine samples (overnight collections) collected longitudinally through study completion for time frame ranging from 2-5 years
Population: Change in Carbamazepine detoxification as a function of age is determined only in patients in the Carbamazepine Phase 2 arm. Changes in Valproic Acid detoxification as a function of age are determined only in patients in the Valproic Acid Phase 2 arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Carbamazepine Phase 2 | Age-related Changes in Bioactivation | 4-Methylthio-2-hydroxyiminostilbene | -0.8876 years^(-1) |
| Carbamazepine Phase 2 | Age-related Changes in Bioactivation | Log (4-Methylthio-2-hydroxyiminostilbene) | -0.0244 years^(-1) |
| Carbamazepine Phase 2 | Age-related Changes in Bioactivation | Fractional Recovery MTHIS | -0.00033 years^(-1) |
| Carbamazepine Phase 2 | Age-related Changes in Bioactivation | Log (Fractional Recovery MTHIS) | -00122 years^(-1) |
| Valproic Acid Phase 2 | Age-related Changes in Bioactivation | Log (5-N-acetylcysteine-3-ene VPA isomers) | -0.0295 years^(-1) |
| Valproic Acid Phase 2 | Age-related Changes in Bioactivation | Log (5-N-acetylcysteine-2-ene VPA) | -0.0250 years^(-1) |
| Valproic Acid Phase 2 | Age-related Changes in Bioactivation | Total N-acetylcysteine conjugates | -0.0296 years^(-1) |
| Valproic Acid Phase 2 | Age-related Changes in Bioactivation | Log (Fractional Recovery NAC-3-ene VPA isomers) | -0.005155 years^(-1) |
| Valproic Acid Phase 2 | Age-related Changes in Bioactivation | Log (Fractional Recovery NAC-2-ene VPA) | -0.000698 years^(-1) |
| Valproic Acid Phase 2 | Age-related Changes in Bioactivation | Log (Fractional Recovery Total NAC conjugates) | -0.005272 years^(-1) |
Comparison: Least squares linear regression evaluating fractional analyte recovery (4-Methylthio-2-hydroxyiminostilbene) as a function of agep-value: 0.004Regression, Linear
Comparison: Least squares linear regression evaluating fractional analyte recovery (Log (4-Methylthio-2-hydroxyiminostilbene) as a function of agep-value: 0.032Regression, Linear
Comparison: Least squares linear regression evaluating fractional analyte recovery (Fractional Recovery (MTHIS)) as a function of agep-value: 0.018Regression, Linear
Comparison: Least squares linear regression evaluating fractional analyte recovery (Log (Fractional Recovery MTHIS)) as a function of agep-value: 0.033Regression, Linear
Comparison: Least squares linear regression evaluating fractional analyte recovery (Log (5-N-acetylcysteine-3-ene VPA isomers)) as a function of agep-value: 0.0004Regression, Linear
Comparison: Least squares linear regression evaluating fractional analyte recovery (Log (5-N-acetylcysteine-2-ene VPA) ) as a function of agep-value: 0.0003Regression, Linear
Comparison: Least squares linear regression evaluating fractional analyte recovery (Total N-acetylcysteine conjugates) as a function of agep-value: <0.0001Regression, Linear
Comparison: Least squares linear regression evaluating fractional analyte recovery (Log (Fractional Recovery NAC-3-ene VPA isomers)) as a function of agep-value: 0.522Regression, Linear
Comparison: Least squares linear regression evaluating fractional analyte recovery (Log (Fractional Recovery NAC-2-ene VPA) ) as a function of agep-value: 0.925Regression, Linear
Comparison: Least squares linear regression evaluating fractional analyte recovery (Log (Fractional Recovery Total NAC conjugates) as a function of agep-value: 0.469Regression, Linear