Biomarkers of CYP2D6 and CYP3A4 Variability in Pediatrics

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Steve Leeder, Children's Mercy Hospital Kansas City
ClinicalTrials.gov Identifier:
NCT01118858
First received: May 6, 2010
Last updated: April 29, 2013
Last verified: April 2013
  Purpose

Cytochrome P450 2D6 (CYP2D6) is an important enzyme in the body for breaking down many medications that are commonly used in children of various ages. The purpose of this proposal is to investigate the relative roles of development and genetic variation in CYP2D6 activity in school-aged children and adolescents with attention deficit and hyperactivity disorder and health controls using the over-the-counter cough suppressant, dextromethorphan or "DM", a standard probe for determining CYP2D6 phenotype. Embedded in the study design are sub-studies to search for by-products of normal body metabolism that reflect differences in enzyme activity, and a pharmacokinetic study to assess the consequences of CYP2D6 genetic variation on the systemic exposure to medications used by this patient population. Ultimately, the goal of the research is to personalize the use of medications in children by selecting the appropriate dose of the correct medication for individual patients.


Condition
Drug Metabolism Phenotype

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Official Title: Exogenous and Endogenous Biomarkers of CYP2D6 and CYP3A4 Variability in Pediatrics

Further study details as provided by Children's Mercy Hospital Kansas City:

Primary Outcome Measures:
  • Characterize the change in CYP2D6 and CYP3A4 phenotype through adolescence [ Time Frame: Three years ] [ Designated as safety issue: No ]
    Growth and development adds an additional level of complexity as the genotype-phenotype relationship may change as children grow and develop. The purpose of this proposal is to characterize the relative roles of ontogeny and genetic variation towards changes in CYP2D6 and CYP3A4 activity during adolescence. Because some drugs commonly used to treat ADHD are metabolized by CYP2D6 and CYP3A4, the information gained from this study will contribute to a better understanding of the dosage requirements of medications used in this patient population.


Secondary Outcome Measures:
  • Identify endogenous markers of CYP2D6 activity [ Time Frame: Three years ] [ Designated as safety issue: No ]
    Metabolomic strategies (HPLC-MS/MS) will be utilized to identify and characterize endogenous compounds that correlate with the formation of dextrorphan (CYP2D6 activity)from the parent compound, dextromethorphan, administered as a phenotyping probe.


Biospecimen Retention:   Samples With DNA

Blood or saliva for DNA testing. Blood samples will be obtained for safety labs throughout the study.


Estimated Enrollment: 220
Study Start Date: April 2010
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Groups/Cohorts
Case
Pediatric patients who have a primary diagnosis of ADHD, combined type, hyperactive impulsive, or inattentive type (ADD).
Control
Healthy subjects: Age and gender matched subjects who do not meet any of the exclusion criteria

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   7 Years to 15 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Cases: Pediatric patients who have a primary diagnosis of ADHD, combined type, hyperactive impulsive, or inattentive type (ADD). (110 subjects)

Controls: Age and gender matched subjects who do not meet any of the exclusion criteria (110 subjects)

Criteria

Inclusion Criteria:

  • Males and females between 7 and 15 years of age.

Exclusion Criteria:

  • Inability to have blood drawn for the screening lab tests
  • Current therapy with medications metabolized by or known to inhibit CYP2D6: *fluoxetine (Prozac®)

    • sertraline (Zoloft®)
    • paroxetine (Paxil®)
    • venlafaxine (Effexor®)
    • risperidone (Risperdal ®)
    • imipramine
    • nortriptyline
    • desipramine
    • amitriptyline
    • fenfluramine
    • terbinafine
    • loratadine (Claritin®)
    • cyclobenzaprine
    • haloperidol (Haldol®)
    • metoprolol
    • quinidine
    • propafenone (Rythmol®)
    • cimetidine (Tagamet®)
    • tamoxifen
    • over-the-counter diphenhydramine-containing drugs
    • including Benadryl and generics and the cough and cold preparations Allegra®
    • Dytuss®
    • Tusstat®
    • Robitussin®
    • pro-drugs codeine
    • tramadol
    • hydrocodone
    • oxycodone (Percodan®, Percocet®) that are converted by 2D6 into their active forms.
  • Illicit drug use, treatment within the past 2 months with paroxetine or fluoxetine, or the past six months with terbinafine are also exclusion criteria.
  • Inability or unwillingness to fast 2 hours prior to the study session
  • Existence of diagnosis which may influence absorption and gastric emptying; such as reflux , inflammatory bowel disease, or Crohn's disease.
  • A demonstrated adverse reaction to previous dextromethorphan exposure
  • Impaired hepatic or renal activity, or physical examination as determined by the Sub Investigator's discretion.
  • Pregnancy
  • Body-mass index (BMI) <5th and >95th percentile
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01118858

Locations
United States, Missouri
The Children's Mercy Hospital
Kansas City, Missouri, United States, 64108
United States, Washington
The University of Washington
Seattle, Washington, United States, 98195
Sponsors and Collaborators
Children's Mercy Hospital Kansas City
Investigators
Principal Investigator: Steven Leeder, PharmD, PhD The Children's Mercy Hospital
  More Information

No publications provided

Responsible Party: Steve Leeder, Pharm.D; Ph.D., Children's Mercy Hospital Kansas City
ClinicalTrials.gov Identifier: NCT01118858     History of Changes
Other Study ID Numbers: 1R01HD058556-01A1, 1R01HD058556-01A1
Study First Received: May 6, 2010
Last Updated: April 29, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Children's Mercy Hospital Kansas City:
CYP2D6
CYP3A4
cytochrome P450
children
pediatrics
dextromethorphan
phenotype
genotype

ClinicalTrials.gov processed this record on August 26, 2014