A wide range of medicines are used outside their licensed indications in children, the doses often being extrapolated from adult data. A recent survey of hospitalised children in five European countries (including the UK) indicated that almost half of all drug prescriptions were either unlicensed or off-label (Conroy et al., 2000). There are ethical difficulties in performing traditional pharmacokinetic and dose ranging studies in children to gain information on drug kinetics and dynamics. The aim of the present research programme, is to measure drug plasma concentrations in blood samples from children who have already been prescribed drugs outside their license, to assess the pharmacodynamics of the drug at the time of sampling and to use sparse data analysis to develop kinetic/dynamic profiles of the drugs under examination and from these to develop evidence based dosage guidelines. The blood samples are usually being taken for another purpose e.g. for the performance of a clinical laboratory test.

The study has received ethical approval and is ongoing. The drugs under examination include: ranitidine, cisapride, diclofenac, enalapril, codeine, paracetamol, spironolactone, midazolam and omeprazole which are unlicensed in the indications or specific age groups of children under investigation. HPLC microanalyses have been developed to allow quantification of drug concentrations in the small blood samples available e.g. Hare et al., (2001). To date a total of almost 800 blood samples, with matched pharmacodynamic data sets, have been collected from a total of 380 infants/children. A minimum of 160 samples per drug are required to allow generalisable results to be obtained. This number has now been reached for two drugs i.e. diclofenac and ranitidine. Preliminary analysis in the case of diclofenac has, for example, shown that in children the volume of distribution is linearly related to weight, clearance is a function of weight to the power 0.73 and that there is no differences in parameter estimates between oral and rectal administration. The estimated half life for a 10kg child is 1.12 hours.

The research programme currently involves pharmacy, medical and nursing staff at two major teaching hospitals sited in Belfast and Liverpool, but funding permitting, this will be extended to further centres to allow a more rapid achievement of the required numbers of patient samples and to specialist units with large numbers of children suffering from specific illnesses e.g. rheumatic disease.

References

Conroy S, Choonara I, Impicciatore P,Mohn A, Arnell H, Rane A, Knoppel C, Seyberth H, Pandolfini C, Rafaelli MP, Rocchi F, Bonati M, Jong G and van der Anker J (2000) Survey of unlicensed and off-label drug use in paediatric wards in European countries. Brit. Med. J., 320, 79-82.

Hare LG, Millership JS, Collier PS, McElnay JC, Carson DJ and Shields M (2001) The use of polymeric solid phase extraction and HPLC analysis for the determination of ranitidine in routine plasma samples obtained from paediatric patients. J. Pharm. Pharmacol., 53, 1265-1272.