Dose estimation for children.

Abstract

There is a wide perception that the paediatric population has been badly served by pharmaceutical companies, drug regulators and governmental funding bodies, in that too little resource has been committed to developing effective and safe medicines for children, and in particular defining the right dose(s) for appropriate paediatric populations (see for example reference [1]). Paediatricians, clinical pharmacologists and clinical pharmacists have for many years struggled to make the best use of information available to them, as evidenced by local paediatric formularies, and, more recently, the formulary published by the Medicines Committee of the Royal College of Paediatric and Child Health and the Neonatal and Paediatric Pharmacists Group [2]. This review explores three areas of this problem: Is this perception true? Does it matter? What is the evidence of harm? If it does matter, what can be done about it? Is it true? With some notable exceptions, the vast majority of drugs have been developed for use in adult populations. The reasons for this have been well explored already [1, 3–7] and include ethical objections to conducting clinical trials in children, the resource (expense and time) that is required to discover and develop new drugs where the use in paediatric populations represents a poor return on investment, and the uncertainty of types of clinical trials in children that will satisfy both regulatory authorities and prescribers as to the efficacy, safety and quality of new potential medicines. It is worth considering this latter point in some detail. Defining the optimal dose, the dose range for a given patient population, and the dose adjustments required as a result of physiological, pathological or iatrogenic interventions (such as drug interactions) remains one of the most challenging tasks in drug development and clinical care. It is not uncommon that the dose or dose range for a given drug established at the time of marketing authorization is significantly modified with experience in clinical practice. Adjustments are most frequently downwards (e.g. treatment of essential hypertension) [8]. Often these dose changes for adult populations take many years to establish. Further, it is only with the passage of time and clinical experience that differences in dose–response in populations emerge; for example, the greater response in young white hypertensives to β-blockers, compared with older and black patients. The realization of defining ‘the right drug for the right patient (at the right dose)’, according to genotypic and phenotypic profile for the vast majority of drugs lies well into the future. Our ignorance of the inherent heterogeneity of an apparently homogeneous group of adult patients has served us rather well for many commonly used drugs, especially for those drugs with wide therapeutic ratios and whose pharmacokinetic variables are well understood. One major stumbling block for dose estimation in children is the very definition of the word ‘children’. Most guidelines now use the age bands recommended in Licensing Medicines for Children 1996, a joint report of the British Paediatric Association and the Association of the British Pharmaceutical Industry [9]; namely newborn (birth to 1 month), 1 month to 2 years, 2–12 years and 12–18 years. The drug monograph on Medicines for Children, prepared by the Medicines Committee of the Royal College of Paediatric and Child Health and the Neonatal and Paediatric Pharmacists Group [2], expresses dosing using these age bands. The monograph also highlights another problem: what units should be used. In Medicines for Children specific doses are generally stated on a per weight or by an age/weight basis. Occasionally, doses are stated on a specific ‘dose/surface area basis’[2, 10]. It is presumed that these dosages are based on the information in the Summary of Product Characteristics (SPC) provided by the pharmaceutical companies, and supplemented by information from ‘off-label’ use in clinical trials and in clinical practice.