Corresponding author: Professor P. Smits, Department of Phar macology, University of Nijmegen, P. O. Box 9101, 6500 HB Nijmegen, The Netherlands Abbreviations: KATP channel, Adenosine-5 '-triphosphate-sen sitive potassium channel; SU, sulphonylurea; FBF, forearm blood flow; SNP, sodium nitroprusside; FVR, forearm vascular resistance; MAP, mean arterial pressure; NIDDM, non-insu lin-dependent diabetes mellitus.

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BackgroundSeveral paediatric physiologically-based pharmacokinetic (PBPK) models have been developed that incorporate developmental changes affecting plasma drug concentrations. Disposition into cerebrospinal fluid (CSF) is also age-related and influenced by physiological factors, including CSF production rate, but also by brain diseases, such as meningitis, which are associated with impaired blood-brain barrier integrity. Our aim was to develop a paediatric brain PBPK model to predict CSF drug concentrations in children with and without meningitis.MethodsA paediatric PBPK model was developed incorporating age-appropriate parameters and associated inter-individual variability. The model was validated for paracetamol, ibuprofen, flurbiprofen and naproxen, and for a paediatric meningitis population by estimating meropenem blood-brain barrier penetration using sensitivity analysis. Plasma and CSF drug concentrations derived from literature were used to perform visual predictive checks and to calculate ratios between simulated and observed AUCs in order to evaluate model performance.ResultsSimulated data were comparable to observed over a broad age range (1 day - 15 y postnatal age), for all drugs investigated. The ratios between observed and simulated AUCs were within 2-fold difference both in plasma and in CSF, indicating acceptable model performance. Disposition of meropenem into the brain was slow and CSF concentrations were lower compared to plasma concentrations. In addition, several days were needed to achieve CSF steady-state concentration.ConclusionsOur paediatric brain PBPK model provides a new tool to predict CSF concentrations in children with and without meningitis and can be used as a template model for other drugs acting in the CNS.Disclosure(s)Nothing to disclose

BackgroundDrug transporters and metabolizing enzymes located in the epithelial lining of the intestine limit or enhance systemic drug exposure. During child development, the abundance and activity of these transporters and enzymes - determining how fast and how much of a drug is being absorbed into the circulation - changes from birth to adolescence. As most drugs given to children are taken by mouth, the aim of this project is to study the abundance and activity of transporters and metabolizing enzymes, involved in the intestinal absorption of drugs.MethodsThe ex vivo Ussing chamber with pediatric small intestinal tissue is applied to evaluate intestinal drug absorption and metabolism.1 Transport and metabolism of a selection of drug molecules is assessed across these tissues by sampling the donor and receiver compartment at different intervals and sample analysis by LC-MS/MS. Viability, functionality and integrity of the tissues are monitored using electrophysiological parameters (dP, R, I). Ussing chamber experiments are combined with a targeted proteomics approach to quantify drug transporter and metabolizing enzyme abundance in these tissues.ResultsAn Using chamber method has been successfully set up using both adult and pediatric intestinal tissue. To date samples from three children of different ages have been evaluated and show promising results. Tissue from the same patients has been stored for proteomics analysis.ConclusionThe Ussing method presents an innovative, feasible approach to study active intestinal transport in children. Further studies are now underway to elucidate age-related variation in intestinal transport and metabolism.ReferenceSjöberg Å, Lutz M, Tannergren C, Wingolf C, Borde A, Ungell AL:Comprehensive study on regional human intestinal permeability and prediction of fraction absorbed of drugs using the Ussing chamber technique. Eur J Pharm Sci 2013 Jan 23;48(1–2):166–80.Disclosure(s)The collaboration project is financed by the Ministry of Economic Affairs by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships. Johan Nicolaï, Richard Mbasu and Anna-Lena Ungell are employees of UCB Biopharma SPRL.