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doi:10.1111/jpc.12802

REVIEW ARTICLE

Fifty years of paediatric clinical pharmacology David Reith1 and Sean Beggs2 1 Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand and 2Department of Paediatrics, Royal Hobart Hospital, School of Medicine, University of Tasmania, Hobart, Tasmania, Australia

The safe and effective use of medicines is a key part of the medical management of children. Paediatric clinical pharmacology is the study of drugs in children with the aim of maximising this safe and effective use. When considering the changes that have occurred over the last 50 years, what first comes to mind is the vast increase in the range of available drugs and the new classes of drugs now available. However, there have also been considerable changes in the science underpinning the new therapeutics and in our understanding of how to use old drugs. Advances in fields such as oncology have come not only from the development of targeted therapies but also from an improved understanding of how to use older drugs (e.g., understanding genetic polymorphisms in thiopurine methyltransferase has improved the use of thiopurines). Paediatric clinical pharmacology is about translating knowledge about drugs from adults to children and improving the use of currently available drugs in children. The most commonly used drugs in current paediatric practice were not available 50 years ago. Paracetamol, currently the most widely used simple analgesic in children, was first marketed in the USA in 1950 but was not commonly used in Australia until the 1970s (and it is still not clear how it exerts its effects). Carbamazepine was first marketed in 1962 and valproate in 1967. Penicillin was available, but not amoxycillin which was first marketed in 1972. Salbutamol was first marketed in the UK in 1968. Human insulins, produced using recombinant technology, were available from the 1980s. Biological agents such as the anti-tumour necrosis factor agents also became available in the last 20 years. Pharmacogenomics promises the development of new drugs using information derived from the human genome. Hence, the methods for identifying and developing new drugs have broadened.

Key Points 1 Paediatric clinical pharmacology contributes to optimizing therapeutics. 2 The sciences underpinning therapeutics have changed greatly in the past 50 years. 3 Paediatric clinical pharmacologists have a role in translating science and influencing health policy. Correspondence: Associate Professor David Reith, Discipline of Paediatrics, Dunedin School of Medicine, PO Box 913, Dunedin 9001, New Zealand. Fax: 0015 64 3 474 7817; email: [email protected] Conflict of interest: None. Accepted for publication 23 September 2014.

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There have been major changes in the regulation of drugs over the past 50 years, beginning with concerns about the quality of manufacturing and progressing through concerns about safety (adverse drug reactions) and requirements for proof of efficacy. All these contribute to an understanding of the risk benefit profile of a drug and enable consumers to make an informed choice. Around 50 years ago, there was the thalidomide tragedy.1 In Australia, this led to the establishment of the Adverse Drug Reactions Advisory Committee, recently renamed the Advisory Committee on the Safety of Medicines, and in New Zealand to the establishment of the Medicines Adverse Reaction Committee. These initiatives were paralleled in the USA and Europe. More recently, in recognition of the paucity of data underpinning paediatric therapeutics, the US has introduced initiatives to encourage drug development for children, paralleled in Europe by the introduction of the requirement for Paediatric Investigation Plans for drugs with potential uses in children. There have been huge advances in our understanding of the fields of pharmacokinetics (PK), pharmacodynamics (PD), drug metabolism and disposition (drug transporters), pharmacogenetics and pharmacoepidemiology. Paediatricians have contributed to developments in all of these fields. The first monograph on pharmacogenetics was published by Werner Kalow in 1962.2 This recognised the genetic contribution to variability in drug metabolism, particularly acetylator phenotype. Since that time there has been the description of a large number of drug metabolising enzymes and recognition of genetic variability contributing to functional differences in many of them. These include CYP2D6, a member of the cytochrome P450 mixed-function oxidase system important for the effects of codeine and for the risks of opioid overdose in breastfed babies of mothers who are ultra-rapid metabolisers. Genetic variability is also important with glucuronidation. There have also been advances in the understanding of the metabolic pathways involved in drug metabolism and how these are different in children, and particularly neonates, compared with adults. The cytochrome P450 system is an example of this: it generally has very low activity in neonates, compared with toddlers and older children. This has led to improved understanding of medication dosing in neonates. Knowledge regarding transport of drugs across biological membranes is undergoing a revolution, greatly enhancing our knowledge of drug disposition and also drug interactions. Transporters are expressed in the gut, liver, kidney and blood–brain barrier and are over-expressed in tumour resistance to chemotherapy. Bioavailability is mostly determined both by enzymatic metabolism and transporters in the gut, and is susceptible to

Journal of Paediatrics and Child Health 51 (2015) 28–29 © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

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drug interaction. Some drugs, e.g. metformin and organic cation transporters, require transporters to be absorbed in order to enter cells and exert their effects and to be excreted from the body. Advances in computing and statistics have enabled the development of new methods for analysing PK and PD data, evolving into the field of pharmacometrics.3 These, combined with sparse sampling strategies, enable the study of PK and PD within a population of patients, rather than the older methods of withinsubject analyses. Sparse sampling strategies are particularly useful in children, where the collection of numerous plasma concentrations for an individual analysis is unpleasant for the child and technically challenging. The effects of characteristics such as body size, maturation, enzyme genotype and disease status upon PK and PD can be studied. This can lead to insights into inter-individual variability in drug effect and to new dosing strategies. Clinical pharmacology is important to medical education.4 Undergraduates require a sound grounding in the sciences underpinning therapeutics, as do trainees of the Royal Australasian College of Physicians. Continuing medical education has also undergone changes in the last 50 years, with clinical pharmacologists contributing to programmes such as the National Prescribing Service in Australia and Best Practice Advocacy Centre in New Zealand. Prescribing resources such as the Australian Medicines Handbook Children’s Dosing Companion and the New Zealand Formulary for Children require input from clinical pharmacologists. As clinical decision support evolves, an understanding of inter-individual variability in response to drugs and the potential for drug–drug, drug–food and drug– herbal interactions will be crucial. Despite the importance of clinical pharmacology to the development of new drugs and the better use of older drugs, the field

Fifty years of pharmacology

is still in its infancy, and there is considerable scope for expansion.5 The ideal dosing of some commonly used medicines in children, and particularly neonates, is still unknown (e.g. vancomycin). Although there is an established training program through the RACP, there are few Paediatric Clinical Pharmacologists in practice in Australia and New Zealand. Most tertiary paediatric hospitals do not have the field represented and have difficulty identifying a process for establishing the field. Although the field contributes greatly at a national level, through input into pharmaceutical policy, there is no path to access national funding. Devolution of health funding to the states has disadvantaged a national strategy. However, because clinical pharmacologists offer skills in clinical medicine, academia and health policy, there are advantages for public hospitals and universities to engage with them, and hence an assured future role for the field. There remains a significant amount that clinical pharmacologists can contribute to improving the health care of children.

References 1 Wiedemann HR. Himweis auf eine derzeitige, Häufung hypo-und aplastischer Fehlbildunger der Gliedmassen. Med. Welt 1961; 37: 1863–6. 2 Kalow W. Pharmacogenetics: Heredity and the Response to Drugs. Philadelphia and London: WB Saunders, 1962. 3 Lesko LJ, Schmidt S. Individualization of drug therapy: history, present state, and opportunities for the future. Clin. Pharmacol. Ther. 2012; 92: 458–66. 4 Allegaert K. Pediatric clinical pharmacology: an introduction to a series of educational papers. Eur. J. Pediatr. 2013; 172: 289–92. 5 Choonara I, Sammons H. Paediatric clinical pharmacology in the UK. Arch. Dis. Child. 2014; 99: 1143–6.

Journal of Paediatrics and Child Health 51 (2015) 28–29 © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)

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