Paediatric Accelerator Mass Spectrometry Evaluation Research Study

Understanding the pharmacokinetics (PK) of drug metabolism in children is essential in determining therapeutic dosages and avoiding adverse events. However to obtain paediatric PK data particularly in the 0-2 year old age group is technically challenging. We therefore propose to develop and validate new approaches to obtain paediatric PK data in this age group using three model drugs viz. paracetamol, spironolactone and midazolam with the ultrasensitive bioanalytical technique, Accelerator Mass Spectrometry (AMS), which can measure parent drug and metabolite concentrations in very small volume blood samples. AMS requires the administration of a microtracer of 14C-labelled drug and hence all the necessary ethical, legal, regulatory and scientific procedures will need to be developed to allow AMS studies in the paediatric population. Intensive blood sampling procedures will be used in a relatively few paediatric patients (up to 100 patients split across two paediatric clinics) to obtain high quality PK data; these data will be compared with literature PK data where sparse sampling procedures have been used. Paediatric patients will be recruited in Tartu, Estonia, and Liverpool, UK. The PAMPERS model drugs will be given as part of normal clinical management; in order to facilitate recruitment, we will therefore recruit patients in environments which cause the least discomfort and do not lead to significant changes in clinical procedures, for example in the post-operative period or in the intensive care unit. 14C-Labelled certificated drugs will be provided by PRI, Poland and ethical and project management aspects by groups who have been previously involved in EU funded programmes. AMS bioanalysis will be performed at a new TNO AMS centre in Zeist, The Netherlands. The innovative procedures developed here will provide a better understanding of the utility of AMS to obtain paediatric PK data and could pave the way for AMS studies to be incorporated into Paediatric Investigation Plans. This would ultimately have the benefit of earlier introduction of new therapies to the paediatric population in a safer, more effective and efficient manner with appropriate dosage regimes.