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Pharmacogenomic Testing in Children

Pharmacogenomic testing (PGx) in children for complex cases beats trial and error, according to research presented by Pharmacy Practice News, with tests yielding actionable results in 9 out of 10 pediatric patients.

“Pharmacogenomic testing in children with complex medical histories can help predict and prevent adverse drug reactions, improve adherence, and salvage drugs with high toxicity,” wrote Gina Shaw in an article published in July 2022.

The former director of the clinical pharmacogenomics service at Boston Children’s Hospital (BCH), Shannon Manzi, PharmD, BCCPS, said that 57 percent of patients have a significant finding from pharmacogenomic testing, while another 36 percent of patients do not have a significant finding to the original question but receive a significant incidental result when the entire panel is examined, yielding a 92+ percent actionable result rate for PGx in pediatrics.

Studying How a Patient’s Genome Can Influence Response to Medicine

Pharmacogenomics, according to the Genomic Medicine Service Alliance, is the study of how a patient’s genome can influence how they respond to medicines. Pharmacogenomics is like pharmacogenetics, except it typically involves the search for variations in multiple genes that are associated with variability in drug response.

Pharmacogenetics is the study of how variation in a single gene can impact variability in the body’s response to one specific medicine (or a group of medicines).

“Pharmacogenomics can examine the entirety of the genome, rather than just single genes, and can examine genetic variation among large groups of people within the population, for example to see how different drugs might affect different ethnic groups,” says the Genomic Medicine Service Alliance. “Both pharmacogenetics and pharmacogenomics support personalized healthcare where medication is tailored to the individual, considering the person’s particular genetic makeup.”

According to the Pharmacy Practice News article, Dr. Manzi noted that Cystic fibrosis (CF) is a condition that is particularly amenable to pharmacogenomic testing and is one of several disorders for which the testing is mandatory. She cited ivacaftor (Kalydeco, Vertex), which can only be prescribed in CF patients with CF transmembrane conductance regulator variants.

“Most of our patients have a complex history involving significant failure to respond to medications or a laundry list of adverse drug reactions with the trial-and-error method,” said Dr. Manzi at a 202a clinical meeting.

Pediatric Pharmacogenomics: Challenges and Opportunities

The Sanford Children’s Genomic Consortium, a partnership of 10 children’s hospitals across the U.S. committed to the innovation and advancement of genomics in pediatric care, published a white paper in 2021 that summarized the challenges and opportunities in PGx and pediatrics.

“A review of published work by several of the early implementers of pediatric-focused clinical PGx programs as identified on the CPIC website indicates wide variability in genotyping methodologies ranging from single gene assays to panels covering greater than 200 genes,” said the White Paper authors.

Some of the pioneers in PGx and pediatrics:

  • St. Jude Children’s Research Hospital opened a clinical research protocol called PG4KDS in 2011 that established preemptive PGx testing as a standard of care. According to Nature: “Investigators at St. Jude have demonstrated the clinical utility of preemptive PGx testing for TPMT in patients with acute lymphoblastic leukemia receiving 6-mercaptopurine and for CYP2D6 in their sickle cell population where codeine is used in the management of pain crises.”

  • Children’s Minnesota health system began a clinical program in 2016 based on the PG4KDS model, leading them to develop custom rules for 10 genes and 26 medications with point-of-care alerts to guide medication selection and dosing.

  • Other PGx pediatric projects have been reported at the University of Florida (focused gene implementations by the University of Florida include TPMT/thiopurines and CYP2C19/proton pump inhibitors (in partnership with Nemours Children’s Specialty Care, Jacksonville, FL and Nemours Children’s Hospital, Orlando, FL); Boston Children’s Hospital (eCDS available for TPMT, CYP2C9, CYP2C19, and VKORC1 that is linked to more than 30 medications based upon the CPIC guidelines); and Cincinnati Children’s Hospital Medical Center (development of single gene tests as well as specialty genotyping panels for psychiatry, opioids, and warfarin).

The White Paper says that many of the barriers to implementing PGx in clinical practice for children are the same as for adults, including:

  • The lack of clinician understanding of how to use pharmacogenomic test results in clinical practice.

  • The absence of infrastructure in EHRs to store structured genetic data.

  • The lack of portability of data when patients are seen in multiple health systems.

  • Concerns about cost and insurance reimbursement.

Specific challenges to children and adolescents in PGx include:

  • Effect of maturation on pharmacogenomic phenotypes.

  • Paucity of pharmacogenomic data obtained in pediatric populations (requiring extrapolation of adult data).

  • Differences in disease states between children and adults where medications with pharmacogenomic implications may be utilized.

“Healthcare providers working with children and adolescents have long recognized that there are developmental changes that impact response to medications,” says the White Paper’s authors. “Historically, finding evidence-based information to guide the use of medications in children and adolescents is an ongoing challenge for pediatric healthcare workers.”

Moving Forward: Strategies for Advancing Pediatric PGx

The White Paper from Sanford Children’s Genomic Medicine Consortium concludes with strategies for advancing clinical pediatric PGx, including:

  • Standardization of Practice: With established consortia like CPIC, PharmGKB, IGNITE, and eMERGE currently leading standardized implementation efforts, partnership with these groups should be pursued to advance the interests of children and adolescents in the standardization of clinical PGx practice.

  • Multi-site Demonstration Project: To date, most published work describes PGx implementation projects at single institutions. Consortia-wide demonstration projects may identify new challenges and implementation models for larger health systems.

  • Pharmacogenomic Databases: As noted above, a large part of the evidence justifying the use of PGx results in children and adolescents is extrapolated from adult data. Because of maturation or different disease states, this extrapolation may not always be appropriate. To this end, the creation of a pediatric PGx registry/database should be considered.

  • Workforce Training and Development: While not restricted to pediatrics, one of the largest existing barriers is the lack of standard practice models and experiential training available for medical professionals. The consortium is poised to consider projects to evaluate practice models, perhaps including collaborations between pharmacists and genetic counselors where each discipline may bring their expertise to the clinic/bedside to advance prescriber and patient understanding of clinical PGx.

  • Payer Engagement. Another benefit of creating a consortium PGx registry will be to facilitate pediatric-focused PGx research further expanding the evidence available to provide evidence-based data for use by insurance payors in assessing the benefits of clinical PGx testing.

“The short and long-term benefits to children (and potentially expectant mothers), the growing body of evidence, and the declining costs of testing technologies for multiple genes should positively influence the uptake of (or utilization) testing,” wrote Dr. Susanne B. Haga in Pharmacogenomics and Personalized Medicine. “However, the clinical utility of PGx results is likely to remain limited until more pediatric PGx trials are conducted and a greater understanding of the multiple factors that can impact drug response is attained, especially in younger children who have not attained stable expression of many genes important to drug metabolism and transport.”