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Developmental Regulation of Proteins Responsible for Transforming Drugs in the Body

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ClinicalTrials.gov Identifier: NCT00117715
Recruitment Status : Completed
First Posted : July 8, 2005
Results First Posted : August 14, 2017
Last Update Posted : September 12, 2017
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Steve Leeder, Children's Mercy Hospital Kansas City

Tracking Information
First Submitted Date July 6, 2005
First Posted Date July 8, 2005
Results First Submitted Date April 4, 2017
Results First Posted Date August 14, 2017
Last Update Posted Date September 12, 2017
Study Start Date October 2000
Actual Primary Completion Date January 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: August 11, 2017)
  • Change in CYP2D6 Drug Metabolism Phenotype With Age [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
Original Primary Outcome Measures Not Provided
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Developmental Regulation of Proteins Responsible for Transforming Drugs in the Body
Official Title Developmental Regulation of CYPs 1A2, 2D6, 3A4
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.

Study Type Observational
Study Design Observational Model: Case-Only
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
Urine DNA (source: blood or saliva)
Sampling Method Probability Sample
Study Population Healthy children 12 months of age at study entry. Followed longitudinally until 5 uears of age.
Condition Healthy
Intervention Procedure: Genotyping 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.
Study Groups/Cohorts Not Provided
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: April 29, 2013)
121
Original Enrollment
 (submitted: July 7, 2005)
150
Actual Study Completion Date January 2010
Actual Primary Completion Date January 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria

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
Sex/Gender
Sexes Eligible for Study: All
Ages 12 Months to 5 Years   (Child)
Accepts Healthy Volunteers Yes
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT00117715
Other Study ID Numbers PPRU 10390
Internal IRB #P00 06-46
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Steve Leeder, Children's Mercy Hospital Kansas City
Study Sponsor Children's Mercy Hospital Kansas City
Collaborators Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
Principal Investigator: J. Steven Leeder, Pharm. D, Ph.D. Children's Mercy Hospital Kansas City
PRS Account Children's Mercy Hospital Kansas City
Verification Date August 2017