Healthy
Conditions
Keywords
Developmental regulation of CYPs 1A2, 2D6, 3A4, Ontogeny, pharmacokinetics, drug biotransformation, enzymatic biotransformation of drugs
Brief summary
This is a drug metabolism study in one-year old children involving caffeine and dextromethorphan.
Detailed description
For many years, it has been considered dogma that drug biotransformation capability is limited at best in the fetus and newborn but increases over the first year of life to levels in toddlers and young children that generally exceed adult capacity. There are several situations where examination of clinical PK data has revealed discernable patterns of drug clearance that can be attributed to developmental differences in drug biotransformation. It has become apparent that there are developmental differences in expression among drug metabolizing enzyme families (cytochromes P450 or CYPs, etc.) Furthermore, individual drug metabolizing enzymes with in a family may have unique developmental profiles that influence the therapeutic response, desired or undesired, to a given agent. All subjects will have a single 5 ml venous blood sample taken upon admission to the study. All subjects will be given a single oral dose of caffeine and dextromethorphan. Patients will be allowed to consume their normal age appropriate diet around the time of study drug administration and through the sample collection periods. All spontaneously voided urine will be collected for a period of 12 hours following the caffeine and dextromethorphan administration The specific aim of this proposal is to extend the current longitudinal investigation into the preschool age group (1 to 5 years of age). The developmental profile of CYPs, 1A2, 2D6, and 3A4 will be determined by caffeine and dextromethorphan phenotyping procedures. The purpose of this study is to determine the age/developmental stage at which the CYP2 1A2, 2D6 and 3A4 activities exceed adult activities.
Interventions
PROCEDUREGenotyping and Phenotyping using dextromethorphan and caffeine as probes
Single doses of dextromethorphan (0.3 mg/kg)and caffeine (3.0 mg/kg) are administered and urine is collected overnight for measurement of drug and metabolites to determine drug biotransformation activity.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Children's Mercy Hospital Kansas City
Study design
Observational model
CASE_ONLY
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
12 Months to 5 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy children 12 months of age at enrollment
Exclusion criteria
* Height and weight ratio outside of the 5th to 100th percentile for adjusted age * Historical and/or biochemical evidence of hepatic, renal, or hematopoetic dysfunction * Historical or physical evidence of a neurologic disease/condition (excluding simple, febrile seizures) * Historical or physical evidence of any disorder associated with swallowing and/or gastrointestinal function * Concomitant therapy with drugs or other products known to alter the activity of hepatic or intestinal microsomal enzymes(e.g., inducers or inhibitors of CYPs 1A2, 2D6, and/or 3A4), P-glycoprotein or potential competing substrates for the CYPs, under study within 7 days of a scheduled phenotyping evaluation * Evidence of behavioral, developmental, or psychosocial conditions in the subjects and/or parents/caregivers that, in the opinion of the investigator, would have the potential to adversely impact the level of compliance required for successful study completion * Evidence of geographic instability (i.e., moving of primary residence within last 24 months) that would adversely influence compliance with repeated study visits necessary for completion of the protocol * Lack of telephone access required to insure adequate subject contact/follow-up * Inability to obtain written informed consent from the subject's parents/guardians
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in CYP2D6 Drug Metabolism Phenotype With Age | every 6 months for 5 years | Concentrations of dextromethorphan(DM) and it's metabolite dextrorphan (DX) are quantified in urine and used to estimate the activity of cytochromes P450 2D6 using the well established DM/DX ratio. The longitudinal study design allows for changes in drug metabolism activity as a function of age which can be characterized via least squares regression where the slope of age vs. DM/DX ratio is examined for deviations from zero. |
| Change in CYP3A4 Drug Metabolism Phenotype With Age | every 6 months for 5 years | Concentrations of dextromethorphan (DM) metabolites 3-hydroxymorphinan (3HM) and dextrorphan (DX) are quantified in urine and used to estimate the activity of cytochrome P450 3A4 using the well established 3HM/DX ratio. The longitudinal study design allows for changes in drug metabolism activity as a function of age which can be characterized via least squares regression where the slope of age vs. 3HM/DX ratio is examined for deviations from zero. |
| Change in CYP1A2 Drug Metabolism Phenotype With Age | every 6 months for 5 years | Concentrations of caffeine metabolites 5-Acetylamino-6-amino-3-methyluracil (AAMU), 1-methylxanthine (1MX), 1-methyluric acid (1MU), and 1,7-dimethyluric acid (17MU) are quantified in urine and used to estimate the activity of cytochrome P450 1A2 using the well established (AAMU+1MX+1MU)/1,7U ratio. The longitudinal study design allows for changes in drug metabolism activity as a function of age which can be characterized via least squares regression where the slope of age vs. (AAMU+1MX+1MU)/1,7U ratio is examined for deviations from zero. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Longitudinal Assessment Cohort Normal healthy children approximately one year of age followed through five years of age to evaluate the ontogeny of CYP1A2, CYP2D6, CYP3A4. | 111 |
| Total | 111 |
Baseline characteristics
| Characteristic | Longitudinal Assessment Cohort |
|---|---|
| Age, Continuous | 1.21 years STANDARD_DEVIATION 0.28 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 107 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 58 Participants |
| Race (NIH/OMB) More than one race | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 46 Participants |
| Sex: Female, Male Female | 52 Participants |
| Sex: Female, Male Male | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 111 |
| other Total, other adverse events | 0 / 111 |
| serious Total, serious adverse events | 0 / 111 |
Outcome results
Primary
Change in CYP1A2 Drug Metabolism Phenotype With Age
Concentrations of caffeine metabolites 5-Acetylamino-6-amino-3-methyluracil (AAMU), 1-methylxanthine (1MX), 1-methyluric acid (1MU), and 1,7-dimethyluric acid (17MU) are quantified in urine and used to estimate the activity of cytochrome P450 1A2 using the well established (AAMU+1MX+1MU)/1,7U ratio. The longitudinal study design allows for changes in drug metabolism activity as a function of age which can be characterized via least squares regression where the slope of age vs. (AAMU+1MX+1MU)/1,7U ratio is examined for deviations from zero.
Time frame: every 6 months for 5 years
Population: Participants completing each milestone visit at each 0.5 years of age.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Longitudinal Assessment Cohort | Change in CYP1A2 Drug Metabolism Phenotype With Age | Log ((AAMU+1MX+1MU)/1,7U) Milestone 7 | -0.822 unitless ratio | Standard Deviation 0.142 |
| Longitudinal Assessment Cohort | Change in CYP1A2 Drug Metabolism Phenotype With Age | Log ((AAMU+1MX+1MU)/1,7U) Milestone 9 | -0.821 unitless ratio | Standard Deviation 0.167 |
| Longitudinal Assessment Cohort | Change in CYP1A2 Drug Metabolism Phenotype With Age | Log ((AAMU+1MX+1MU)/1,7U) Milestone 1 | -0.851 unitless ratio | Standard Deviation 0.185 |
| Longitudinal Assessment Cohort | Change in CYP1A2 Drug Metabolism Phenotype With Age | Log ((AAMU+1MX+1MU)/1,7U) Milestone 2 | -0.823 unitless ratio | Standard Deviation 0.17 |
| Longitudinal Assessment Cohort | Change in CYP1A2 Drug Metabolism Phenotype With Age | Log ((AAMU+1MX+1MU)/1,7U) Milestone 3 | -0.858 unitless ratio | Standard Deviation 0.204 |
| Longitudinal Assessment Cohort | Change in CYP1A2 Drug Metabolism Phenotype With Age | Log ((AAMU+1MX+1MU)/1,7U) Milestone 4 | -0.856 unitless ratio | Standard Deviation 0.15 |
| Longitudinal Assessment Cohort | Change in CYP1A2 Drug Metabolism Phenotype With Age | Log ((AAMU+1MX+1MU)/1,7U) Milestone 5 | -0.832 unitless ratio | Standard Deviation 0.168 |
| Longitudinal Assessment Cohort | Change in CYP1A2 Drug Metabolism Phenotype With Age | Log ((AAMU+1MX+1MU)/1,7U) Milestone 6 | -0.853 unitless ratio | Standard Deviation 0.169 |
| Longitudinal Assessment Cohort | Change in CYP1A2 Drug Metabolism Phenotype With Age | Log ((AAMU+1MX+1MU)/1,7U) Milestone 8 | -0.851 unitless ratio | Standard Deviation 0.17 |
Comparison: Univariate analysis (ANOVA) of the change in log ((AAMU+1MX+1MU)/1,7,U) over timep-value: 0.831ANOVA
Primary
Change in CYP2D6 Drug Metabolism Phenotype With Age
Concentrations of dextromethorphan(DM) and it's metabolite dextrorphan (DX) are quantified in urine and used to estimate the activity of cytochromes P450 2D6 using the well established DM/DX ratio. The longitudinal study design allows for changes in drug metabolism activity as a function of age which can be characterized via least squares regression where the slope of age vs. DM/DX ratio is examined for deviations from zero.
Time frame: every 6 months for 5 years
Population: Participants completing each milestone visit at each 0.5 years of age.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Longitudinal Assessment Cohort | Change in CYP2D6 Drug Metabolism Phenotype With Age | Log (DM/DX) Milestone 9 | -2.384 unitless ratio | Standard Deviation 0.672 |
| Longitudinal Assessment Cohort | Change in CYP2D6 Drug Metabolism Phenotype With Age | Log (DM/DX) Milestone 1 | -1.974 unitless ratio | Standard Deviation 0.593 |
| Longitudinal Assessment Cohort | Change in CYP2D6 Drug Metabolism Phenotype With Age | Log (DM/DX) Milestone 2 | -2.083 unitless ratio | Standard Deviation 0.617 |
| Longitudinal Assessment Cohort | Change in CYP2D6 Drug Metabolism Phenotype With Age | Log (DM/DX) Milestone 3 | -2.162 unitless ratio | Standard Deviation 0.638 |
| Longitudinal Assessment Cohort | Change in CYP2D6 Drug Metabolism Phenotype With Age | Log (DM/DX) Milestone 4 | -2.073 unitless ratio | Standard Deviation 0.657 |
| Longitudinal Assessment Cohort | Change in CYP2D6 Drug Metabolism Phenotype With Age | Log (DM/DX) Milestone 5 | -2.161 unitless ratio | Standard Deviation 0.669 |
| Longitudinal Assessment Cohort | Change in CYP2D6 Drug Metabolism Phenotype With Age | Log (DM/DX) Milestone 6 | -2.185 unitless ratio | Standard Deviation 0.67 |
| Longitudinal Assessment Cohort | Change in CYP2D6 Drug Metabolism Phenotype With Age | Log (DM/DX) Milestone 7 | -2.284 unitless ratio | Standard Deviation 0.745 |
| Longitudinal Assessment Cohort | Change in CYP2D6 Drug Metabolism Phenotype With Age | Log (DM/DX) Milestone 8 | -2.177 unitless ratio | Standard Deviation 0.699 |
Comparison: Univariate analysis (ANOVA) of the change in log(DM/DX) over timep-value: 0.035ANOVA
Primary
Change in CYP3A4 Drug Metabolism Phenotype With Age
Concentrations of dextromethorphan (DM) metabolites 3-hydroxymorphinan (3HM) and dextrorphan (DX) are quantified in urine and used to estimate the activity of cytochrome P450 3A4 using the well established 3HM/DX ratio. The longitudinal study design allows for changes in drug metabolism activity as a function of age which can be characterized via least squares regression where the slope of age vs. 3HM/DX ratio is examined for deviations from zero.
Time frame: every 6 months for 5 years
Population: Participants completing each milestone visit at each 0.5 years of age.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Longitudinal Assessment Cohort | Change in CYP3A4 Drug Metabolism Phenotype With Age | Log (3HM/DX) Milestone 4 | -0.158 unitless ratio | Standard Deviation 0.276 |
| Longitudinal Assessment Cohort | Change in CYP3A4 Drug Metabolism Phenotype With Age | Log (3HM/DX) Milestone 6 | -0.136 unitless ratio | Standard Deviation 0.194 |
| Longitudinal Assessment Cohort | Change in CYP3A4 Drug Metabolism Phenotype With Age | Log (3HM/DX) Milestone 7 | -0.133 unitless ratio | Standard Deviation 0.164 |
| Longitudinal Assessment Cohort | Change in CYP3A4 Drug Metabolism Phenotype With Age | Log (3HM/DX) Milestone 8 | -0.122 unitless ratio | Standard Deviation 0.202 |
| Longitudinal Assessment Cohort | Change in CYP3A4 Drug Metabolism Phenotype With Age | Log (3HM/DX) Milestone 9 | -0.169 unitless ratio | Standard Deviation 0.218 |
| Longitudinal Assessment Cohort | Change in CYP3A4 Drug Metabolism Phenotype With Age | Log (3HM/DX) Milestone 1 | -0.069 unitless ratio | Standard Deviation 0.18 |
| Longitudinal Assessment Cohort | Change in CYP3A4 Drug Metabolism Phenotype With Age | Log (3HM/DX) Milestone 2 | -0.117 unitless ratio | Standard Deviation 0.194 |
| Longitudinal Assessment Cohort | Change in CYP3A4 Drug Metabolism Phenotype With Age | Log (3HM/DX) Milestone 3 | -0.142 unitless ratio | Standard Deviation 0.223 |
| Longitudinal Assessment Cohort | Change in CYP3A4 Drug Metabolism Phenotype With Age | Log (3HM/DX) Milestone 5 | -0.109 unitless ratio | Standard Deviation 0.201 |
Comparison: Univariate analysis (ANOVA) of the change in log(3HM/DX) over timep-value: 0.194ANOVA