P – Pharmacogenomics
Pharmacogenomics looks at how a person's genetic make-up can affect how a body responds to medications and focuses on combining knowledge on pharmacology, pharmacokinetics and genetics. The genetics aspect centres on genes and their specific functions – known as genomics.
Every prescriber knows that there are usually some risks in prescribing medications, but some patients may not feel the full benefit of the drug or suffer different adverse drug reactions (ADRs) compared to other people (Parry and Hawcutt, 2020). Cytochrome P450 enzymes (CYPs) often have an impact on metabolism in different drugs: these enzymes are coded by genes – and these can vary in the general population (Royal Pharmaceutical Society (RPS), 2022). Having ‘normal’ or ‘abnormal’ enzymes can potentially affect how a drug could be metabolised. An individual's genetic make-up will not change over time, but the expression of that information can actually change from the neonatal period through to adolescence (Bashore and Trinkman, 2015).
As children develop, organs such as the liver or kidneys will develop further and enzymatic pathways will also develop, inevitably resulting in a variability between patients’ pharmacokinetic responses. It is clear that there are differences in responses between children and adults, although studies in children are limited. The continued clarification of genes being identified, which can affect pharmacological treatment of childhood diseases, can only increase the ability to predict drug treatment response in children.
Probably the most common drug that has been affected by the understanding of pharmacogenomics is codeine. The World Health Organization (WHO) ‘Pain ladder’ (WHO, 2020) implements a step-wise approach to pain management, which includes codeine. However, CYP2D6 – a polymorphic enzyme which metabolises many drugs – can be expressed differently in different people, resulting in a slower or a faster metabolism (Rieder and Carleton, 2014). Codeine is converted into morphine by CYP2D6. Some people (who are known as ultra-rapid metabolisers) convert codeine into morphine faster than others, resulting in higher morphine levels in the blood, which can cause respiratory depression: children have been shown, post-mortem, to have been shown to be ultra rapid metabolisers (Tobias et al, 2016). Due to this, codeine is now longer licensed to treat children under 12 years of age in the UK (MHRA, 2014).
Children undergoing treatment for cancer therapy have also been studied: loss of function variants of the thiopurine 5-methyltransferase (TPMT) and nudix hydroxylase 15 (NUDT15) genes can increase the concentration of thiopurine active metabolites, resulting in a lower tolerance of thiopurine drugs for treat ment for acute lymphoblastic leukaemia in children (Hoshitsuki et al, 2021), such as azathioprine or mercaptopurine. Similarly, with methotrexate and the methylenetetrahydrofolate reductase (MTHFR) enzyme, which has been shown to have polymorphic variants. One variant can be seen in up to 10% of caucasian populations, resulting in a higher incidence of toxicity.
In respiratory medicine, a new drug Ivacaftor is approved for children over the age of 2 years with cystic fibrosis with specific gene mutations (Parry and Hawcutt, 2020), accounting for up to 5% of cystic fibrosis patients. Children with asthma are commonly treated with beta 2 agonists such as salbutamol during an asthma exacerbation, which acts on the beta 2 adrenergic receptor (ADRB2). Yet a commonly seen polymorphism in the ADRB2 gene coding region can actually have mixed results in the effectiveness of salbutamol, when combined with inhaled corticosteroids (Bashore and Trinkman, 2015).
Other disease systems are also affected, such as in paediatric rheumatology and the use of methotrexate, and also in patient with attention deficit hyperactivity disorder (ADHD), and dopamine transporters. The DAT1 gene on chromosome 5 has been associated with response to methylphenidate, a central nervous system stimulant to treat ADHD (Bashore and Trinkman, 2015), commonly known as ritalin.
Implementing pharmacogenomic testing in children to inform prescription decision making may not be relevant to every child, but it is certainly in place in many haematology-oncology settings with regards to the thiopurine drugs (Barker et al, 2022). Ethically, issues of consent or assent may be pertinent, surrounding clear understanding of the testing, or if other secondary information is obtained from the testing (Rieder and Carleton, 2014), which may have an impact on health insurance or care management, particularly in the USA. However, with newer arrays, such as whole genome sequencing, more targeted approaches avoid incidental findings (Vanakker and De Paepe, 2013).
It is clear that further research in this field will enable pharmacogenomic guided dosing and prescribing in children, and it is hoped that this article has given a brief overview of an insight into current and future practices. An understanding of pharmacogenomics can enable prescribers to confidently and safely predict responses to drugs at different ages and different genetic make ups (Bashore and Trinkman, 2015). The potential for implementing pharmacogenomic testing within specialised – and perhaps routine healthcare – could potentially be implemented further in the years to come (Barker et al, 2022).