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April 04, 2017 – Personalized medicine, also referred to as precision medicine, incorporates the individual patient’s characteristics into treatment, rather than relying on population means. Over the past several years, it has become a significant focus for research. Developments in pharmacogenomics, the study of genomic variations that influence response to drugs, has accounted for much of the recent work in this area. In fact, as of the end of 2016, in the US, the prescribing information for about 200 drugs approved by the Food & Drug Administration (FDA) included guidance on using pharmacogenomics information in drug selection or dosing. Understanding and incorporating genomic variation, however, is just one component of providing precision medicine. Age, gender, environment, and comorbidities are only a few of the potential factors to be considered in providing personalized pharmacotherapy.
In this context, it is good to see that research in pediatric precision medicine, i.e., concerning children, including pharmacogenomics, is growing at a rapid rate. A 2015 review of the FDA’s pharmacogenomics biomarker labeling data identified 38 drugs with information pertinent to use of the drug in pediatric patients. There are currently also 137 identified pediatric pharmacogenomic studies listed on Clinicaltrials.gov.
Information generated from studies in adults often can be of value in treating children, such as the identification of the correlation of human leukocyte antigen B variant allele HLA-B*1502 and carbamazepine-induced Stevens Johnson Syndrome or toxic epidermal necrolysis and the role of thiopurine methyltransferase polymorphisms in the development of thiopurine-induced bone marrow suppression.
Recent examples of indications where pharmacogenomic studies have played a role in the better understanding of genetic backgrounds of pediatric patients and will already in the short term result in according clinical treatment(s), including guidelines may include Asthma (1), Attention Deficit Hyperactivity Disorder (ADFD) (2), Autism (3), Cardiac Transplantation (4), Epilepsy (5), Infectious Diseases (6), Pain Management (7, 8), and Sickle Cell Disease (9, 10), to mention a few. Overall, a number of variants of genes such as CYP2D6, GYLX-13, mTOR, GRIN21, KCNT1, SCN2A, SCN8A, rs3812718, UGZB7, OPRM+ and OCT1, among others, have been identified as actionable targets of personalized therapy approaches in children, and there are more to come.
A very impressive example of the roe of genetic variation in children is the case of metabolism of Codeine to Morphine as catalyzed by CYP2D6. In the CYP2D6 ultrarapid metaboliser phenotype of patients (i.e., carriers of the CYP2D6*2xN allelic variants), this conversion from Codeine to Morphine is enormously more pronounced than in the CYP2D6 extensive and slow metaboliser phenotypes (i.e. the “normal patients” for this transformation. CYP2D6 ultrarapid metaboliser phenotype of patients may attain systemic levels of Morphine in this process which may lead to Morphine-induced breathing difficulties that can be fatal. This has led to cases of deaths and serious adverse events in children who took the drug after a tonsillectomy and/or adenoidectomy and were ultra-rapid metabolizers of codeine (see the FDA Safety Communication and an earlier article by thasso). Children of different ethnic background may have a very different risk for this Codeine-induced life-threatening adverse event; While in Northern European descendants, the prevalence of the CYP2D6*2xN allelic variant is at 1 – 2 % only, it is at 29% in an African / Eritrean population. This may be substantial information to be aware of for a pediatric clinician when prescribing Codeine-containing treatments to children in mixed populations.
As for pharmacogenomics in children in practice, however: Parents may want to exercise some caution when genotyping their children for therapy selections. A recent paper from Bowdin et.al., at the SickKids Genome Clinic, describes the interprofessional approach to incorporating pharmacogenomic data into patient care in the clinic setting (11). The paper provides and in-depth look at the challenges and benefits of developing a clinic to focus on individualized therapy based on pharmacogenetic data. The authors address currently available laboratory testing and the challenges of obtaining clinically relevant data in a useful format, as well as the need for collaboration among clinics. They also highlight the need for genetic counseling and call attention to the potential impact of genetic testing of children on their future employment and insurance coverage. This latter issues have not yet been sufficiently addressed by the society as a whole nor by the legal system(s).