CYP2D6 Pharmacogenetics in Risperidone-Treated Children

CYP2D6 PHARMACOGENETICS IN RISPERIDONE-TREATED CHILDREN AND ADOLESCENTS WITH PSYCHIATRIC OR NEURODEVELOPMENTAL DISORDERS

Risperidone is an important medication used to treat children with psychiatric illnesses or neurodevelopmental disorders, such as autism. Despite excellent symptom control, the potential for side effects is worrisome. Treating these disorders is difficult because not everyone responds the same way to the same risperidone dose. One reason for this is genetic differences in how people break down the drug. Understanding these differences will help clinicians choose a dose and better predict the response so patients will be treated successfully with a lower risk for side effects. This study will research these genetic differences in children with psychiatric or neurodevelopmental disorders. Hypothesis: The inter-patient variability in risperidone pharmacokinetics and exposure, adverse events, and clinical response in patients with psychiatric or neurodevelopmental disorders is associated with identifiable pharmacogenetic factors, such as CYP2D6 single nucleotide polymorphisms (SNPs).

Study Overview

• Status: Completed
• Conditions: Neurodevelopmental Disorders; Psychiatric Disorders

• Study Type: Observational
• Enrollment (Actual): 47

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Subjects will include up to 41 risperidone-treated children and adolescents with psychiatric or neurodevelopmental (ND) disorders who participated in one of two previous risperidone pharmacokinetics investigations.

To have a larger sample of poor metabolizer subjects, we plan to enroll at least 8 additional subjects who are on stable treatment with risperidone, and perform risperidone pharmacokinetics analyses. Prospectively enrolled subjects (n = 8) will be CYP2D6 poor metabolizers and will include White / Caucasian subjects, of any socioeconomic status, and will be recruited from inpatients or outpatients at Cincinnati Children's Hospital

Description

Inclusion Criteria:

• Previous risperidone PK study participation (CCHMC, Rainbow Babies and Children's Hospital or OSU)
• CYP2D6 PM predicted phenotype
• Actively taking risperidone
• Under 18 years of age at time of enrollment
• Signed, dated informed consent forms

Exclusion Criteria:

• Investigators are unable to contact the subject/legal guardian(s)
• Subject is no longer taking risperidone
• CYP2D6 predicted phenotype other than PM
• Subject is non-White, with respect to race, for PK study participation
• Subject is 18 years of age or older
• Subject is less than 5 years of age
• Subject is pregnant at the time of the full PK study
• Subject/legal guardian unwilling or unable to participate in the study

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Poor metabolizers; Patients with CYP2D6 genotypes predictive of poor metabolizer phenotype
Non poor metabolizers; Patients with CYP2D6 genotypes predictive of intermediate, extensive, or ultra-rapid metabolizer phenotypes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
association of common CYP2D6 polymorphisms with risperidone area under the curve	pre-dose (sample 1 = 0-30 minutes before first oral dose), and three at well-timed post-dose points (sample 2 = 15-30 minutes after dose; sample 3 = 60-90 minutes after dose; sample 4 = 4-6 hours after dose)

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: Ohio State University; Rainbow Babies and Children's Hospital
• Investigators: Principal Investigator: Shannon N Saldana, PharmD, MS, Children's Hospital Medical Center, Cincinnati

Publications and helpful links

General Publications

• Aman MG, Vinks AA, Remmerie B, Mannaert E, Ramadan Y, Masty J, Lindsay RL, Malone K. Plasma pharmacokinetic characteristics of risperidone and their relationship to saliva concentrations in children with psychiatric or neurodevelopmental disorders. Clin Ther. 2007 Jul;29(7):1476-86. doi: 10.1016/j.clinthera.2007.07.026.
• Cabovska B, Cox SL, Vinks AA. Determination of risperidone and enantiomers of 9-hydroxyrisperidone in plasma by LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Jun 1;852(1-2):497-504. doi: 10.1016/j.jchromb.2007.02.007. Epub 2007 Feb 15.
• Sherwin CM, Saldana SN, Bies RR, Aman MG, Vinks AA. Population pharmacokinetic modeling of risperidone and 9-hydroxyrisperidone to estimate CYP2D6 subpopulations in children and adolescents. Ther Drug Monit. 2012 Oct;34(5):535-44. doi: 10.1097/FTD.0b013e318261c240.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): June 1, 2011

Study Registration Dates

• First Submitted: October 31, 2008
• First Submitted That Met QC Criteria: October 31, 2008
• First Posted (Estimate): November 2, 2008

Study Record Updates

• Last Update Posted (Estimate): December 11, 2012
• Last Update Submitted That Met QC Criteria: December 10, 2012
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Risperidone; Autism; Pharmacogenetics; Psychiatric disorders; Neurodevelopmental disorders
• Additional Relevant MeSH Terms: Behavioral Symptoms; Pathologic Processes; Disease; Problem Behavior; Mental Disorders; Neurodevelopmental Disorders
• Other Study ID Numbers: 2008-0659; SPR104683