Developmental Regulation of Proteins Responsible for Transforming Drugs in the Body

Developmental Regulation of CYPs 1A2, 2D6, 3A4

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

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Procedure: Genotyping and Phenotyping using dextromethorphan and caffeine as probes

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
• Enrollment (Actual): 121

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 5 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

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

Description

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

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• 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

Study record dates

Study Major Dates

• Study Start: October 1, 2000
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): January 1, 2010

Study Registration Dates

• First Submitted: July 6, 2005
• First Submitted That Met QC Criteria: July 7, 2005
• First Posted (Estimate): July 8, 2005

Study Record Updates

• Last Update Posted (Actual): September 12, 2017
• Last Update Submitted That Met QC Criteria: August 11, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: pharmacokinetics; drug biotransformation; Ontogeny; Developmental regulation of CYPs 1A2, 2D6, 3A4; enzymatic biotransformation of drugs
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Purinergic Antagonists; Purinergic Agents; Respiratory System Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Antitussive Agents; Dextromethorphan; Caffeine
• Other Study ID Numbers: PPRU 10390; Internal IRB #P00 06-46