Genomics exam #3 - pediatrics

Pharmacogenomics in Pediatrics

Introduction to Laura Ramsey

  • Name and Title: Laura Ramsey, PhD, Section Chief for Individualized Therapeutics, Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation.

  • Contact Email: lramsey@cmh.edu

  • Education:

    • Bachelor of Science from the University of Northern Iowa.

    • PhD from the University of Minnesota with focus on immunology, specifically B cell development.

    • Experience at St. Jude Children’s Research Hospital (Memphis, TN) in pharmacogenetics.

  • Professional Background:

    • 8 years at Cincinnati Children’s Hospital focusing on pharmacogenetics research and implementation.

    • 2 years at Children’s Mercy, serving as Section Chief and co-director of Clinical Pharmacology Fellowship program (T32).

Overview of Children’s Mercy Kansas City

  • Type: Non-profit independent children’s hospital.

  • Established: 1897.

  • Personnel:

    • 8,000+ employees.

    • 800+ faculty members.

    • 3,000+ nurses.

    • 1,000+ allied health professionals.

    • More than 700 volunteers.

Pediatric Health System Statistics

  • Hospital Capacity and Services:

    • 390 beds.

    • 335,734 outpatient visits annually.

    • 202,496 emergency and urgent care visits annually.

    • 14,345 admissions annually.

    • 19,469 surgeries annually.

    • 5,942 patient transports annually.

Opportunities for Pharmacogenomics (PGx) Utility in Pediatrics

  • Commonly Prescribed Drugs with Genetic Variability:

    • Thiopurines (e.g., mercaptopurine, thioguanine, azathioprine).

    • SSRIs (e.g., sertraline, escitalopram, citalopram).

    • Carbamazepine.

    • Tacrolimus.

    • Ondansetron.

    • Codeine.

  • Key Situations for PGx Use:

    • When there is a risk of serious adverse events related to drug metabolism variants.

    • For drugs with a narrow therapeutic index.

    • When dose titration based on clinical response is inadequate.

    • For serious diseases where under-treatment poses significant risk.

    • When adverse events or response are hard to monitor.

Drug Metabolizing Enzyme Phenotypes

  • Measurement of drug concentration can reveal metabolizer phenotypes which inform PGx utility.

    • Enzyme phenotypes include: Poor Metabolizer (PM), Intermediate Metabolizer (IM), Normal Metabolizer (NM), Rapid Metabolizer (RM), and Ultrarapid Metabolizer (UM).

Pharmacogenetics Lifecycle

  • Stages:

    1. Discovery and allele definition conducted through PharmVar.

    2. Preclinical and clinical research to assess function compiled by ClinPGx.

    3. Guideline development by organizations such as CPIC and DPWG.

    4. Implementation in clinical practice.

    5. Outcomes research to evaluate effectiveness.

Developmental Aspects of PGx

  • Variability: Expression of drug metabolizing enzymes changes during developmental phases from neonates to adolescents.

  • Off-label Usage: Many medications are used off-label in pediatric populations, affecting pharmacodynamics and efficacy.

  • Literature Reference: Ramsey et al. J Am Acad Child Adolesc Psychiatry, 2020.

Prevalence of Medications with CPIC Guidelines Prescribed to Pediatric Patients

  • Study Parameters:

    • Research conducted from 2011 to 2017 at 16 sites.

    • Prescribing rate: Approximately 3 million prescriptions per year, translating to 8-10K per 100K pediatric patients.

  • Statistics:

    • Total PGx prescriptions: 1,335 per 100K annually, with 2,200 changes in PGx prescriptions per year due to variability.

Pediatric Prescribing Study Findings

  • Variability in Prescribing Rates:

    • Range of prescriptions across sites: 1,000 to 30,000 prescriptions per 100,000 patients.

    • Approximately 20% of those prescribed received two or more CPIC level A medications annually.

  • Most Commonly Prescribed Drugs:

    • Ondansetron.

    • Opioid analgesics.

    • SSRIs.

    • Immunosuppressants.

  • Actionability:

    • Highest actionability drugs: opioid analgesics, ondansetron, SSRIs, TCA (Tricyclic Antidepressants).

    • Source: Ramsey et al. JAMA Netw Open, 2020.

Medicaid Prescribing Study Findings

  • Duration: 2011-2019.

  • Population: 2-4.6 million youths prescribed annually.

  • Prevalence: 13.9-17.9% received at least one PGx drug each year.

Implementation Insights in Pediatrics

  • Survey to Children’s Hospital Association:

    • 13 hospital respondents indicated implemented PGx tests included:

    • TPMT testing for thiopurines (69%).

    • CYP2C19 testing for voriconazole (54%).

    • CYP2D6 testing for codeine/opioids (54%).

    • CYP2D6/CYP2C19 testing for SSRIs (46%).

  • Barriers to Implementation:

    • Major barriers included:

    • Cost concerns.

    • Reimbursement issues.

    • Clinical decision support inadequacies.

    • Provider knowledge deficits.

    • Lack of randomized controlled trials (RCTs) to support PGx testing.

Survey Implementation Results

  • Survey Sent to PGRN Members:

    • 43 respondents categorized as pediatric only, adult only, or both.

    • All sites tested CYP2C19; all pediatric sites tested for TPMT, NUDT15, CYP3A5, CYP2D6, and CYP2C9.

Evidence for Gene-Drug Pairs in Pediatrics

  • Moderation: Medication; Gene; CPIC Level; ClinPGx Level; Pediatric PK Association; Pediatric Response Data; Pediatric Implementation Trial.

    • Thiopurines:

    • Gene: TPMT; CPIC Level: A; ClinPGx Level: 1A.

    • Gene: NUDT15; CPIC Level: A; ClinPGx Level: 1A.

    • Tacrolimus:

    • Gene: CYP3A5; CPIC Level: A; ClinPGx Level: 1A.

    • Voriconazole:

    • Gene: CYP2C19; CPIC Level: A; ClinPGx Level: 1A.

    • SSRIs:

    • Drugs: Escitalopram, Sertraline; Gene: CYP2C19; CPIC Level: A; ClinPGx Level: 1A.

    • Atomoxetine:

    • Gene: CYP2D6; CPIC Level: A; ClinPGx Level: 1A.

    • Codeine:

    • Gene: CYP2D6; CPIC Level: A; ClinPGx Level: 1A.

    • PPIs:

    • Gene: CYP2C19; CPIC Level: A; ClinPGx Level: 1A.

  • References include Relling et al., Annual Review of Pharmacology and Toxicology, 2019.