Tamara van Donge

Chapter 1 16 concentrations vary tremendously due to large inter- and intraindividual variability. 18,19 The availability of reference ranges for any biomarker to support clinical decision- making and tailor therapy to the individual patient will greatly support neonatal and pediatric care. 20,21 Pediatric pharmacotherapy The development of age-dependent reference ranges for biomarkers, together with the investigation of PK properties of a drug in the neonatal and pediatric population can be considered as a first crucial step to optimize pediatric pharmacotherapy and to ensure the right dose for every individual patient. The PK of a drug can vary in the neonatal and pediatric population as compared to adults because of maturational developments, and therefore a tailored dosing strategy must be achieved for this particular population. Pediatric drug dosing is still frequently based on body weight since this parameter is often assumed as a marker of maturation and is easily accessible in a clinical setting. The extrapolation of dosing regimens from adults to newborns solely based on body weight is very simplistic, keeping in mind that in newborns alone there is a ten-fold variability in birth weight (0.5 kg to 5 kg). Body size or weight has been the most frequently used parameter for growth and is characterized by a linear relationship, although the ontogeny of drug-metabolizing enzymes or the maturation of the kidney function is not always characterized by such a relationship. Over the last decades, innovative approaches (e.g. pharmacometric modeling and simulation of PK/PD data) have been investigated and applied to derive more safe and effective treatment for the entire pediatric population, which will be discussed further in more detail. In general, there are three main reasons why we need model-informed dosing optimization in newborns, infants and children; I. There is still a lack of knowledge on the PK of drugs in the pediatric population resulting in suboptimal efficacy and toxicity. II. Current dosing regimen are quite complex and therefore prone to error. III. There is a low target attainment rate with current dosing regimen. Pediatric drug development and regulation The drugs that enter the (adult) market have been subjected to thorough and exhaustive investigation of the Health Authorities to ensure the products are effective to treat the symptoms of the disease, are safe to ensure minimum side effects and are of high quality. The question arises, why would we need model-informed dosing optimization strategies if these drugs have already been subjected to multiple clinical studies and assessments?