Individualized genome-based therapy has the potential to impact drug efficacy, reduce rates of toxicity and improve overall outcomes for children with a variety of medical disorders. When 70% of medications used in children today have not been adequately studied in children [2
], the use of PGx technology to better understand drug effects is especially promising in pediatrics. PGx data, coupled with an understanding of the nongenetic factors that impact pediatric drug disposition, including organ function, concomitant medications and underlying diseases processes [3
], can improve our current dosing practices for children. Specific applications and benefits include: pharmacogenetic-guided dosing for children instead of a trial-and-error approach; improved medication effectiveness by appropriate dosing strategies and patient population selection; decreased adverse events by identifying those children at risk of enhanced susceptibility to drug toxicity and variable systemic exposures; an improved understanding of treatment nonresponse; facilitation of drug approval for effective agents by determining drug response and adverse drug reactions in specific patient cohorts; and an improved understanding of pediatric PK and pharmacodynamics (PD) [4
]. PGx testing can provide critical information to explain or describe those factors that influence drug disposition in children including variable absorption (e.g., membrane transporter SNPs [5
], metabolism (e.g., genetic variants encoding drug-metabolizing enzymes such as CYP450 enzymes) [3
], and excretion [6
]. Furthermore, identifying genetic variation in drug targets (e.g., drug receptors) and key regulatory proteins (e.g., ion transporters), which can lead to both direct and indirect effects on drug action [3
], may help to explain a child’s drug response to a particular medication. Importantly, pediatric PGx data, in comparison to with that of adults, needs to be interpreted in the context of the ontogeny of gene products (e.g., drug-metabolizing enzymes and transporters) throughout a child’s development, which will also impact drug disposition and drug effect [6
]. PGx data may also be used to classify children into prognostic categories as demonstrated by the Taiwanese pediatric acute lymphocytic leukemia (ALL) study [8
]. Individual genomic polymorphisms can also be used to better understand the PK/PD variability of drugs used in children; this is well described in pediatric organ transplantation, asthma and attention deficit disorder [9
]. There are also ongoing clinical PGx studies to understand the PGx of adverse drug reactions and how they can be predicted for children with psychiatric and neurodevelopmental disorders, atopic dermatitis, HIV, asthma, sickle cell disease, venous thrombosis and ALL – devastating diseases that afflict many children and demand improved therapies [10
]. While challenges of PGx testing remain, including the incorporation of polygenic determinants of drug effects into an individualized dosing regimen [3
] and the difficulty interpreting several SNPs at the same time, PGx testing holds great promise as a method to improve drug safety and efficacy for children.
One noteworthy example of PGx testing in pediatrics is the use of the thiopurine methyltransferase (TPMT
) genotype and/or enzyme assay results in children with ALL to predict chemo therapy sensitivity. The activity of TPMT, a key enzyme in the metabolic pathway of thiopurines, impacts the safety and efficacy profile of mercaptopurine and thioguanine, two drugs used in the standard treatment for childhood ALL. TPMT
genetic polymorphisms can at least in part explain the considerable differences in toxicities, such as myelosuppression, experienced by children with TPMT
variants that result in reduced expression and activity of this enzyme [11
]. PGx testing can then be used in practice to guide appropriate dosing, a practice which has been demonstrated to impact outcomes for children with ALL [12
]. Another example of PGx in children includes VKORC1
testing in children initiating warfarin treatment [13
]. While these examples illustrate how genotype ana lysis for drug metabolism can help guide therapy in children, the application of PGx testing is far from universal in this population. In fact, leukemia protocols usually only recommend TPMT
testing for children who experience severe myelosuppression, and PGx algorithms for warfarin dosing have not yet been validated in children [14
]. There are many concerns that need to be addressed before the full implementation of PGx testing in children occurs including, but not limited to, the expense of testing, privacy, insurance denials for the cost of testing, unknowns related to the use and storage of genetic information, the failure of genomic testing to predict outcomes and one which is receiving possibly the greatest attention with respect to predictive pediatric PGx testing; the threat of discrimination.
The specific elements related to potential discrimination are based on the following considerations: the ability to afford PGx testing [15
]; the possibility of ethnicity-based testing rather than individualized testing [17
]; and the risk of denials for disability, long-term care and life insurance as a result of testing [20
]. In light of these concerns, should physicians obtain genotype ana lysis for children when the results may uncover predispositions to adult-onset disease or resistance to specific therapies when these findings might impact a child’s ability to get insurance later in life? Fortunately, steps to protect patients who have PGx testing performed have been taken by the US federal government. Specifically, in 2008 the Genetic Information Nondiscrimination Act (GINA) was passed and went into effect in 2009 [21
]. The intent of this legislation was to protect patients from discrimination by their insurance company or employer based on genetic testing results or family history [21
]. However, it can be difficult for clinicians to maintain up-to-date knowledge of PGx policy and legislation, some of which is rather complicated. For example, while the passage of GINA was critical for the protection of adults and children and the advancement of the field of PGx, notable gaps in broad protection exist [21
]. Specifically, it does not protect against discrimination when applying for life or disability insurance [21
], a gap which may have significant implications. In addition, once genetic information of any kind is available, many worry that such information might be used to the detriment of a child sometime in the course of his or her life should legislative protections be weakened. Though the level of risk introduced by such issues remains partially hypothetical, the risk being demonstrable only if they occur in the context of legal and policy development, it is critical to acknowledge these concerns.
Another important concern with PGx testing is how to proceed with secondary or ancillary genomic information. Ancillary information is defined as additional information pertaining to the predisposition to diseases, prognostic information, or information relevant to other classes of drugs for a disease that the individual is not currently seeking treatment [22
]. Ancillary information may also have implications for family members when considering inherited variations. Some test results can also provide information on health events that will occur much later on in a person’s life. For instance, testing for the apolipoprotein E genotype could guide warfarin dosing or statin selection, but may also inform individuals regarding their risk of disease, such as Alzheimer’s disease [23
]. Recommendations should be developed to help guide pediatricians on how best to disclose and manage this clinical information in children. It should be emphasized, however, that while PGx testing may provide secondary information, the primary PGx test should not be discriminatory; rather, the primary information should be used to improve drug therapy.
Despite the benefits of PGx testing in children, challenges remain for both patients and clinicians. For instance, a primary issue in the USA relates to reimbursement and associated healthcare costs. Because third-party payers may refuse to provide PGx testing, it might be available only to those who can afford the costs. The financial impact of the testing will require considerable further study, including cost analysis that attends to such variables as the cost of PGx testing compared with, for example, days in the hospital from neutropenia induced by inappropriately high doses of mercaptopurine. As PGx testing increases in children, clinicians and investigators must continue to explore all the risks and benefits related to pediatric PGx testing in order to inform policy-makers and guide further implementation in routine care and research. Even when patients are willing to accept risks for the sake of potential benefits, they may still be confronted with the additional burden of testing that does not remove or even impact the need to monitor drug safety and efficacy through pre-existing standard of care methods [24
]. Other challenges include the lack of readiness of the healthcare delivery system for personalized medicine, the gap between the genomic medicine technology available and the health system knowledge regarding this technology [25
], and the lack of site-based testing for quick test turnaround time, which can lead to treatment delays. Lastly, pediatricians remain mindful of the fact that genomic analysis performed for a child may have unforeseen implications for the individual once they reach adulthood.
Although PGx testing, which aims to improve drug safety or efficacy, is distinct from predictive genetic testing and mandatory newborn genetic screening, the experience we have gained with traditional genetic testing in children can be instructive. For example, the incorporation of PGx testing may involve a similar approach to that applied to other genetic tests, with integration into pediatric clinical care only after tests have been demonstrated to have analytic validity, clinical validity and clinical utility in adult studies and once evidence-based guidelines for test utilization have been developed [26
]. Some find this level of caution and demonstrated certainty excessive, with the potential harm of delayed PGx benefits to children. In any case, the guiding aim of PGx is ultimately to optimize therapy, and to do so while decreasing unnecessary risk to children.