Developmental Regulation of Proteins Responsible for Transforming Drugs in the Body

NCT00117715 | Completed Results

• 2 other identifiers: PPRU 10390Internal IRB #P00 06-46
• Study Type: observational
• Target: 121
• Locations: 1 country
• Sites: 1

Brief Summary

This is a drug metabolism study in one-year old children involving caffeine and dextromethorphan.

Conditions

Healthy

Keywords

Developmental regulation of CYPs 1A2, 2D6, 3A4; Ontogeny; pharmacokinetics; drug biotransformation; enzymatic biotransformation of drugs

Outcome Measures

Primary Outcomes (3)

• 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.

  every 6 months for 5 years

• 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.

  every 6 months for 5 years

• 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.

  every 6 months for 5 years

Interventions

Genotyping and Phenotyping using dextromethorphan and caffeine as probes PROCEDURE

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.

Eligibility Criteria

• Age: 12 Months - 5 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)
• Sampling Method: Probability Sample

Study Population

Healthy children 12 months of age at study entry. Followed longitudinally until 5 uears of age.

You may qualify if:

• Healthy children 12 months of age at enrollment

You may not qualify if:

• 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

Sponsors & Collaborators

• Children's Mercy Hospital Kansas City: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

Biospecimen

Retention: SAMPLES WITH DNA

Urine DNA (source: blood or saliva)

MeSH Terms

Interventions

Genotype; Caffeine

Intervention Hierarchy (Ancestors)

Genetic Phenomena; Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

Not all enrolled participants were available for evaluation at every milestone.

Results Point of Contact

• Title: J. Steven Leeder
• Organization: Children's Mercy Hospital

sleeder@cmh.edu

816-234-3059

Study Officials

• J. Steven Leeder, Pharm. D, Ph.D.

  Children's Mercy Hospital Kansas City

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Pharm.D; Ph.D.

Study Record Dates

• First Submitted: July 6, 2005
• First Posted: July 8, 2005
• Study Start: October 1, 2000
• Primary Completion: January 1, 2010
• Study Completion: January 1, 2010
• Last Updated: September 12, 2017
• Results First Posted: August 14, 2017

Record last verified: 2017-08

Locations

US (1)