Pharmacogenetics studies how genetic variation impacts pharmacological treatment both in terms of efficacy and drug-induced toxicity. In recent years, there have been substantial advances in the field thanks to the performance of clinical trials and observational studies. However, specific data for the pediatric population is scarce. If we specifically focus on pharmacogenetics, a search in PubMed using the terms ((pharmacogenetics) OR (pharmacogenomics)) AND ((children) OR (pediatrics) OR (pediatry)) yielded a total of 4732 records as of July 19, 2024. In contrast, the search strategy ((pharmacogenetics) OR (pharmacogenomics)) NOT ((children) OR (pediatrics) OR (pediatry)) yielded 34 180 records. This reflects the extent to which the pediatric population is underrepresented in pharmacogenetic trials and, in consequence, the dearth of information currently available to apply pharmacogenetics to pediatric care.

In Spain, two recent milestones have promoted rapid advances in the availability and use of pharmacogenetic tests in the National Health System (NHS). The first one was the approval on June 23, 2023 by the Interterritorial Council of the NHS of the update to the genetic test catalog of the nationwide service portfolio of the public health care system, subsequently ratified by Order SND/606/2024 of June 13, 2024, which includes tests for 672 gene-disease associations or target regions that would be covered for any patient in the NHS, 33 of them in the field of pharmacogenomics. The second was the launch of the pharmacogenomic biomarker database of the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS, Spanish Agency of Medicines and Medical Devices) on July 29, 2024. The aim of this database is to facilitate access to the information contained in summaries of product characteristics (SmPCs) to promote the application of pharmacogenetics to clinical practice.1

It is important to note that none of these initiatives distinguish between adult and pediatric patients, so all drugs and indications included that affect the pediatric population are likely to be applicable to this population. Nevertheless, there are important limitations in this regard. As noted above, the limited evidence from specific studies supporting their clinical utility in the pediatric populations is one of the chief limitations. Another significant limitation involves the impact of the maturation of drug-metabolizing enzymes and transporters on drug response.2 For example, cytochromes CYP2D6 and CYP2C19, which are involved in the metabolism of a large number of drugs, undergo a prolonged maturation process that starts in the fetal period.3 Their enzymatic activity at birth is not equivalent to their activity in adulthood, so the clinical impact of variants in the CYP2C19 and CYP2D6 in the first months of life remains unknown.

The aim of this article is to guide the implementation of pharmacogenetics in pediatric care and contribute to updating the knowledge of pediatric care providers on the relevant pharmacogenetic data currently available for drugs used in the pediatric population. To this end, we conducted an exhaustive review of the pharmacogenomic test catalog of the Ministry of Health and of the AEMPS database, highlighting the frequent indications and uses in the pediatric population. We also reviewed and summarized the recommendations for the implementation of clinical pharmacogenomics in pediatric care included in the main pharmacogenetics guidelines that are currently available, such as those of the Clinical Pharmacogenomics Implementation Consortium (CPIC), the Dutch Pharmacogenetics Working Group and the Spanish Society of Pharmacogenetics and Pharmacogenomics, with particular emphasis on the most useful dosage adjustment recommendations based on the available evidence and the frequency the drugs are used in the pediatric population.

Knowledge of these associations and its appropriate application to the prescribing/contraindication or dosage of these drugs is key in order to improve the safety and effectiveness of treatments in the pediatric population. We hope that this information will be useful and facilitate the implementation of pharmacogenetics in pediatric care.

The pharmacogenomic biomarker database of the AEMPS includes 78 gene-drug pairs for 68 active ingredients involving 18 different genes. According to the website of the AEMPS, the information contained in this database is based on the gene-drug pairs supported by level 1A evidence documented in the database pharmgkb.org as of June 2024 and pairs for whom information is not available in the SmPC but are included in the nationwide genetic and genomic test portfolio of the Spanish Ministry of Health. Table 1summarizes the information for the 19 drugs or drug families and the 12 genes for which the pharmacogenomic test catalog notes the indications for the test.

For the purpose of this review, we summarized the information contained in the AEMPS database as well as the indications authorized in the pediatric population and some of the frequent off-label uses of the included active ingredients (information obtained from SmPCs4 in addition to consultation of the Pediamecum database of active ingredients authorized for use in pediatrics)5 (Table 2). Based on the results of this analysis, there are recommendations for 78 gene-drug pairs, of which nearly 80% (62) correspond to biomarkers included in the nationwide testing portfolio, and another 13% (10) have been proposed for inclusion in it. On the other hand, focusing on the 68 active ingredients in this database, 65% (44) have one or more pediatric indications, and the vast majority are used off-label in this age group.

The table shows whether the drug is authorized for any pediatric indication, and whether the SmPC includes recommendations for dose adjustment or, otherwise, precautions or use based on the pharmacogenomic results.

Of the 19 drugs specifically included in the nationwide catalog, 13 (68%) have authorized pediatric indications: the anti-infectives abacavir, atazanavir, and voriconazole; the anticonvulsants carbamazepine, phenytoin, and oxcarbazepine; the thiopurines (azathioprine and mercaptopurine); omeprazole; ivacaftor; allopurinol; pimozide; and rasburicase. In the case of abacavir, atazanavir combined with voriconazole and ritonavir, ivacaftor, and rasburicase, testing is required prior to treatment, as it determines the indication of the drug (ivacaftor) or a clear contraindication for its use (all others). However, for the rest of the drugs included in the nationwide catalog and most of the drugs in the AEMPS database, the SmPC does not specify whether testing should be performed nor include specific recommendations for dose adjustment. That is why the main scientific societies and expert working groups in pharmacogenetics develop guidelines and consensus recommendations based on the current evidence. These guidelines are essential to guide the implementation of pharmacogenetics in clinical practice.

At present, the CPIC is the pharmacogenetics association with the greatest number of guidelines for dosage adjustment. The article describing its guideline development process specifies that each recommendation includes an assessment of its usefulness in pediatric patients.6 At the time of this writing, the CPIC has published a total of 27 guidelines, of which 24 include at least one section with recommendations adapted to the pediatric population (Table 3). Specifically, there are four drugs for which there are specific dosing recommendations for children: atomoxetine, efavirenz, voriconazole and warfarin. In the rest of the CPIC guidelines, recommendations based on the genotype and phenotype are extrapolated from the adult population, with certain limitations due to the scarcity of the evidence or the immaturity of drug metabolizing pathways in young children.2

Guidelines and consensus documents published by other groups and organizations, such as the Dutch Pharmacogenetics Working Group and the Spanish Society of Pharmacogenetics and Pharmacogenomics do not systematically include an assessment of the usefulness in the pediatric population. At present, they only include specific pediatric dosing information for atomoxetine due to the specific use of this drug in the treatment of attention-deficit/hyperactivity disorder.7,8

We now proceed to a more detailed description of the drug-gene pairs for which CPIC guidelines are available and which are considered most relevant in pediatrics based on the current evidence and the frequent use of the corresponding drug in the pediatric population, following consultation with a group of experts that included pediatricians and hospital-based pediatric pharmacists.

Efavirenz is a nonnucleoside reverse transcriptase inhibitor. It is used to treat human immunodeficiency virus in combination with other drugs in children aged 3 months or older and weighing more than 3 kg. At present, its use in pediatric patients is limited, as there are alternatives with better tolerability. The SmPC notes that patients homozygous for the G516 T CYP2B6 variant may have higher plasma concentrations of efavirenz. The guideline provides dosing recommendations based on the CYP2B6 phenotype and the age and weight of the patient.36

In the case of drugs such as clopidogrel, ondansetron, tricyclic antidepressants, or serotonin reuptake inhibitors, the use of clinical guidelines for dose adjustment is well established in the adult population, but there are few specific pharmacogenetic studies (usually small) on which to base specific recommendations for the pediatric and adolescent population. In addition, the frequent off-label use of these drugs further hinders the availability of evidence specific for these diseases. In most cases, the guidelines mention the possibility of extrapolating adult recommendations based on the pharmacokinetics of drug-gene interaction and the maturation of the involved enzymatic pathways, if use of these drugs is necessary.

The only guidelines that refer to specific recommendations for the pediatric and adolescent populations are the selective serotonin reuptake inhibitors, tricyclic antidepressants, and the recently published beta-blocker guidelines.

In the case of selective serotonin reuptake inhibitors, the guideline indicates that citalopram, escitalopram, and sertraline are the drugs for which the most pharmacogenetic data are available to support gene-based prescribing in pediatric and adolescent populations, although these data are mainly derived from small pharmacokinetic studies.37,38

In respect of amitriptyline, the guideline notes that due to the lower dosage used for treatment of neuropathic pain in pediatric patients (eg, 0.1 mg/kg/day) it is less likely that PMs and IMs will experience adverse effects due to supratherapeutic plasma concentrations of amitriptyline, so dose adjustments are only recommended for indications requiring higher doses.

The beta-blocker guideline mentions two pharmacogenetic studies in the pediatric population, one on the association of ADRB1 and CYP2C9 variants with the efficacy of atenolol and losartan in Marfan syndrome, and another on the impact of CYP2D6 polymorphisms on the efficacy of propranolol for treatment of hemangioma.39,40 However, definite conclusions cannot be drawn based on the results of these studies. The guideline concludes that it may be appropriate, with caution, to extrapolate the recommendations given for the adult population to CYP2D6 and metoprolol (in PMs, initiation with a lower dose and slower progressive titration, watching for the potential development of bradycardia), since the CYP2D6 genotype seems to correlate to enzyme activity from 2 weeks post birth.

Other drugs such as statins, fluoropyrimidines, or tamoxifen are rarely used in the pediatric population, so there are no pharmacogenetic studies or specific recommendations for them. Pharmacogenetic tests are not routinely performed in the pediatric population, but it should be noted that as genotyping techniques advance, prospective testing with broad gene panels is becoming increasingly common. In such cases, the information will be available for future use and will be helpful if the use of these drugs is contemplated.

In the pediatric population, the problems generally encountered in the implementation of pharmacogenetics (lack of training for health care staff, lack of experts in pharmacogenetics, the dispersion of tests among different services, limited interest on the part of hospital administrators, etc) are exacerbated by the dearth of pediatric research establishing differential characteristics in reference to the population normally included in clinical trials and observational studies. Despite these difficulties, the update of the genomic service portfolio, with the inclusion of pharmacogenomics, is a clear boost to its implementation. The creation of multidisciplinary groups to engage in the implementation of pharmacogenetics in each hospital is key, as is the inclusion of pediatric specialists in these groups to ensure the rapid and safe application of pharmacogenetics in the pediatric population.

This research project did not receive specific financial support from funding agencies in the public, private or not-for-profit sectors.