For a small fraction of all therapeutic drugs currently used, routine monitoring is crucial. The reason for this is that the gap between therapeutic and toxic concentration is very narrow. This, combined with the fact that there exists high inter-individual variability, has led to the need for therapeutic drug monitoring (TDM). The goal of TDM is to individualize the dosage to achieve maximum efficacy and at the same time minimize drug toxicity. TDM has obvious clinical benefits for patients and healthcare systems. However, TDM in children is particularly challenging. In addition, traditionally used venipunctures to determine drug concentrations are not well tolerated by children. The goal of this project is to address these challenges by providing a non-invasive and patient-specific solution, whereby drugs requiring TDM in children will be monitored in exhaled breath. We will use a cutting-edge analytical platform (i.e. secondary electrospray ionization-mass spectrometry) available at the University Children's Hospital Basel to detect drugs in breath with unparalleled speed, selectivity and sensitivity. Initially, we will measure simultaneously blood and breath concentrations of drugs routinely monitored in our hospital (e.g. anti-convulsants). We will then use this information as an input to develop pharmacokinetic computational models to predict blood concentrations based on the breath test read-out. During the final phase, we will validate these models in an independent group of patients to proof the clinical transferability of breath-based tests to guide drug dosage on an individual basis. This project will have a tremendous impact on current pediatric TDM clinical practice by: i) enabling a more personalized treatment, hence reducing ineffective doses and adverse effects; ii) improving patients' outcome; iii) saving hospital costs and iv) gaining new insights on pharmacokinetic aspects such as key parameters governing the diffusion of drugs in the lungs.

Exposure of children to environmental tobacco smoke (ETS) can lead to serious health consequences, impairing lung development, and increasing the risk for respiratory disease in adulthood. While there is strong evidence confirming detrimental effects of ETS from clinical observational studies, much remains unknown at the molecular level which could improve our understanding of the mechanisms by which ETS affects respiratory health. ETS has been associated with alterations in cell signaling, ultimately causing impaired cellular growth in lung tissue. The objective of this project is to identify exhaled markers altered as a result of ETS exposure, thus gaining insights on the detrimental effects of ETS. We will measure cotinine levels using standard analytical methods to objectively assess the level of exposure on an individual basis. We will seek associations between systemic cotinine concentrations and exhaled metabolite levels. Obtaining evidence of the detrimental effect of ETS exposure in the respiratory system as assessed by exhaled metabolites will provide a valuable input to public health policymakers.