Clinical trial NCT00117715: Developmental Regulation of Proteins Responsible for Transforming Drugs in the Body
Official title: Developmental Regulation of CYPs 1A2, 2D6, 3A4
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Healthy
Keywords: Developmental regulation of CYPs 1A2, 2D6, 3A4
Ontogeny
pharmacokinetics
drug biotransformation
enzymatic biotransformation of drugs
Lead sponsor: Children's Mercy Hospital Kansas City
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2005-07-08
Enrollment: 121
Sex: ALL
Minimum age (years): 12
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: yes
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Healthy children 12 months of age at study entry. Followed longitudinally until 5 uears of age.

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.

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

Primary outcomes:
measure: Change in CYP2D6 Drug Metabolism Phenotype With Age
timeFrame: every 6 months for 5 years
measure: Change in CYP3A4 Drug Metabolism Phenotype With Age
timeFrame: every 6 months for 5 years
measure: Change in CYP1A2 Drug Metabolism Phenotype With Age
timeFrame: every 6 months for 5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
Study officials:
affiliation: Children's Mercy Hospital Kansas City
name: J. Steven Leeder, Pharm. D, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: