Current perspective on pediatric pharmacogenomics

The goal of pharmacogenomics is to comprehend the effect of inter-individual genetic variations on the outcome of treatment. [1,2] By understanding the role that these genetic variants play in the therapeutic response, safer and more effective individual dosing regimens can be tailored based on patient genetic profile, all in the hope of maximizing the efficacy while minimizing the side effects of treatment. [1,2] This becomes of particular importance in the pediatric population which is more vulnerable to the toxic effects of medications and is subject to age-dependent pharmacokinetics. Since the enzymatic activity of certain drug metabolizing enzymes can vary as a function of age and due to numerous developmental and maturation processes, the ontology of those enzymes and the influence of genetic variants on their activity are essential for the accurate prediction of treatment response in children. [1–4] One of the biggest challenges to treatment in children is the first dose. Clinical essays are far more difficult to carry in children than in adults, and thus, this dose is usually extrapolated by applying scaling approaches to data acquired from dosing essays in adults. This becomes more complicated when considering the influence of inter-individual genetic variation, the maturation of organ systems, and the preferential clearance of certain drugs due to enzymatic expression switches that occur at multiple stages of development (ex. CYP3A7 to CYP3A4 in neonates). [2–4] Recent studies demonstrated that genetically guided personalized therapy holds the promise to deliver a safer and more effective treatment in pediatric organ transplantation. [5,6] One well-described example is the dosing of Tacrolimus (TAC), an immunosuppressant used to reduce organ rejection both in pediatric and in adult patients. Its narrow therapeutic index combined with the significant variability in its pharmacokinetics (which can reach up to 10-fold in children) makes it difficult to set a standardized dosing regimen. [6] While underdosing of TAC can lead to organ rejection, overdosing might lead to an increased risk of infection and other serious side effects. To help explaining some of this variability, pharmacogenomics investigated the impact of genetic variants on the activity of CYP3A5 enzyme – a major metabolizer of TAC. Most notably, in order to maintain a therapeutic blood concentration, patients who are homozygous or heterozygous for the wild-type allele CYP3A5*1 (i.e. CYP3A5 expressers) have 1.5–2 folds higher dose requirements compared to CYP3A5 nonexpressers. CYP3A5 non-expressers are homozygous for the variant-type allele ‘CYP3A5*3’ and have a non-functional protein product. [5,6] That being said, it is important to note that therapeutic drug monitoring remains the standard practice – as demonstrated by many clinical essays – when adjusting the dose of TAC in clinical settings. Prospective trials that prove the clinical added value of genotype-guided therapy (e.g. starting dose selection) are still needed. [6] Similar PG findings apply to the field of pain management. Codeine, for example, is a commonly used analgesic which is converted to its active metabolite, morphine, by the hepatic enzyme CYP2D6. Genetic variations in the CYP2D6 gene include point mutations, insertions, deletions, as well as copy number variants. Some of these variations can lead to protein under-expression or a complete lack of function (like in the example of CYP2D6*4 or CYP2D6*5 alleles), whereas other rearrangements can cause an over-expression like in the case of duplicated (CYP2D6*xN) alleles. [7,8] The presence of two non-functional alleles renders the individuals poor metabolizers of CYP2D6 substrates, while having two reduced function alleles or one non-functional and one reduced activity allele make their carriers intermediate metabolizers. Moreover, extensive metabolizers are defined as the ones carrying two wild-type normal-activity alleles or one of these alleles in combination with a reduced function or a non-functional allele. Finally, those who carry more than two CYP2D6 gene copies are referred to as ultra rapid. [7,8] The need for a better understanding of the codeine pathway found its roots in pharmacogenomics after fatal incidences in clinical practice in which children who were ultra CYP2D6 metabolizers (or their mothers in the case of breast-fed children) have been exposed to an excessive dose of morphine leading to subsequent severe respiratory depression. [7–9] Consequently, the Food and Drug Administration (FDA) communicated a black box warning against codeine use to manage postoperative pain in children and it recommends to use alternate analgesics for CYP2D6 ultra-rapid and poor metabolizers. [10] In cancer therapy, patients routinely receive multi-drug combinations. Since the consequence of treatment failure is frequently life-threatening, the power to predict how a particular patient will respond to a specific treatment protocol is priceless and lies in the core interest of personalized oncology. [1] A lot of noteworthy examples of the usefulness of pharmacogenetics in pediatric oncology can be found in studies of the treatment outcome of acute lymphoblastic leukemia (ALL). Treatment-related toxicity can be life-threatening and is a main cause of treatment interruption or cessation in childhood cancer. [11] In addition, survivors of childhood ALL are at risk of higher treatment-associated morbidity and mortality with a cumulative incidence of chronic health conditions reaching 73.4%. [12] One effective drug used in chemotherapy is 6-mercaptopurine, which is mainly metabolized by the enzyme thiopurine S-methyltransferase (TPMT). Genetic variants in the TPMT gene coding for this enzyme are associated with inactive alleles and reduced enzymatic activity. Studies have shown that *2, *3A, and *3C are the most prevalent TPMT EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, 2016 VOL. 12, NO. 4, 363–365 http://dx.doi. org/10.1517/17425255.2016. 1145656