When Should Pharmacogenomic Results Be Interpreted Differently in Children Than Adults?

Pharmacogenomics (PGx) analyzes genes encoding drug metabolizing enzymes (DMEs) to help predict response and tolerability to medications. These findings can provide additional information to tailor prescribing decisions. Currently, PGx-guided dosing recommendations are focused mainly on the adult population given the limited amount of evidence in pediatrics. The impact of development and maturation of DMEs can create challenges when applying PGx testing to pediatric patients. As such, the developmental pattern, or ontogeny, of these DMEs needs to be considered.

The maturation of DMEs vary by enzyme and isoform. Several DMEs including CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are expressed in the first few weeks of life. Typically, by 1-2 years of age, the activities of these isoenzymes and others are similar to those of adults.¹ However, between 2-12 years of age, there is a surge in isoenzyme activities that exceed typical adult ranges.² By puberty, these activities decrease to adult levels. The activities of these DMEs influence the pharmacokinetics and pharmacodynamics of medications which in turn impacts potential drug-gene interactions. There are several professional resources that provide PGx information and dosing guidelines. Clinical Pharmacogenomic Implementation Consortium (CPIC) is an international consortium that provides evidence-based, peer-reviewed PGx-based dosing recommendations. A majority of these guidelines are specific to adults given the lack of data in pediatrics. While some guidelines recommend against the extrapolation of adult recommendations to children, there are several with the following generalized statement: “… there is no reason to suspect that gene name genetic variation will affect this drug’s metabolism differently in children compared with adults.” There are a few mediations with sufficient PGx evidence in pediatrics allowing for CPIC, the National Comprehensive Cancer Network® (NCCN®), and FDA drug-labeling to provide pediatric-specific dosing recommendations. The CPIC guidelines for voriconazole and atomoxetine have separate adult and pediatric recommendations based on CYP2C19 and CYP2D6 polymorphisms, respectively.^3,4 Additionally, the CPIC guidelines for CYP2B6 and efavirenz are applicable to children ≥ 40 kg and adult patients.⁵ The NCCN Guidelines® for Pediatric ALL recommends PGx testing for TPMT and NUDT15 genes in patients receiving thiopurine therapy.⁶ Moreover, the FDA labels and FDA Table for Pharmacogenetic Associations provide pediatric-specific dosing recommendations for pantoprazole, codeine, tramadol, and pimozide.^7,8

Conclusion

When assessing the PGx test results for a pediatric patient, the age of the patient needs to be considered in order to estimate the maturation of the DMEs. CPIC, FDA labeling, and other PGx professional guidelines can guide the clinician in determining if their published PGx-based recommendations are applicable to children. If a PGx-guided dosing regimen is utilized in a pediatric patient, vigilant monitoring of adverse reaction development and drug efficacy is highly recommended. 

Cathryn Jennissen, PharmD, BCOP is currently the Senior Clinical Pharmacist at OneOme LLC, a med tech company in Minneapolis, MN. OneOme offers additional information and PGx education which can be found at OneOme.com/education or you may reach out to support@oneome.com.

References

1. Lu H, et al. J Pediatri Pharmacol Ther. 2014;19(4):262-76.
2. Anderson GD. Epilepsia. 2002;43 Supple 3:53-9.
3. Moriyama B, et al. Clin Pharmacol Ther. 2017;102(1):45-51.
4. Brown JT, et al. Clin Pharmacol Ther. 2019;106(1):94-102.
5. Desta Z, et al. Clin Pharmacol Ther. 2019;106(4):726-733.
6. NCCN. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pediatric Acute Lymphoblastic Leukemia V.2.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed May 23, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.
7. FDA. See FDA Drug Label. US Food Drug Adm. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm. Accessed May 23, 2023.
8. US Food and Drug Administration. Table of Pharmacogenetic Associations. Available at: https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations. Accessed May 23, 2023.