Pharmacogenomics in Pediatric Patients: Towards Personalized Medicine

Abstract

It is well known that drug responses differ among patients with regard to dose requirements, efficacy, and adverse drug reactions (ADRs). The differences in drug responses are partially explained by genetic variation. This paper highlights some examples of areas in which the different responses (dose, efficacy, and ADRs) are studied in children, including cancer (cisplatin), thrombosis (vitamin K antagonists), and asthma (long-acting β2 agonists). For childhood cancer, the replication of data is challenging due to a high heterogeneity in study populations, which is mostly due to all the different treatment protocols. For example, the replication cohorts of the association of variants in TPMT and COMT with cisplatin-induced ototoxicity gave conflicting results, possibly as a result of this heterogeneity. For the vitamin K antagonists, the evidence of the association between variants in VKORC1 and CYP2C9 and the dose is clear. Genetic dosing models have been developed, but the implementation is held back by the impossibility of conducting a randomized controlled trial with such a small and diverse population. For the long-acting β2 agonists, there is enough evidence for the association between variant ADRB2 Arg16 and treatment response to start clinical trials to assess clinical value and cost effectiveness of genotyping. However, further research is still needed to define the different asthma phenotypes to study associations in comparable cohorts. These examples show the challenges which are encountered in pediatric pharmacogenomic studies. They also display the importance of collaborations to obtain good quality evidence for the implementation of genetic testing in clinical practice to optimize and personalize treatment.

Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants?

“…The inter-individual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs, usually resulting in treatment failure. As a fundamental element in individualized therapy, pharmacogenomics allows for the evaluation of certain genetic variants responsible for drug response and makes better outcome and lower toxicity [ 30 , 31 ]. TPMT genotyping and its implementation in 6-MP toxicity prediction are considered as a great success in this field.…”

Pharmacogenetics of inhaled long‐acting beta2‐agonists in asthma: A systematic review

“…Also shortened response and airway smooth muscle relaxation time in children and faster maximal bronchoconstriction postexercise are characteristics that differ from adults . These differences underline that children should not just be considered “small adults” . Another reason for not observing an effect in adults may be that studies with children have considerable higher numbers compared to the studies conducted in adults.…”

Adverse Drug Reactions in Children: The Double‐Edged Sword of Therapeutics

“…Childhood cancer is one of the main causes of death among children in the developed world. In 2012 the number of children (<15 years of age) diagnosed with cancer worldwide was estimated as 163,000, with an increase in the overall 5‐year survival rate in the US to over 80% . This success has come with a price tag of increased ADRs incidence to chemotherapeutic agents in children .…”