Clinical pharmacological studies in children: From exploratory towards confirmation driven methodology

Just like children are not small adults, pediatric studies are not just subgroup-adult studies. Clinical pharmacology aims to predict these effects based on drug, population and/or patient-specific pharmacokinetics(concentration-time profiles) and-dynamics(concentration-effect profile). The most essential characteristics of childhood are growth and maturation. Both phenomena are most prominent during infancy making the claim that "an infant is not just a small child" as relevant compared to the paradigm that "a child is not just a small adult". From a clinical pharmacology perspective, the consequence of such a dynamic setting is extensive variability throughout childhood in both the pharmacokinetics and pharmacodynamics. Trial design probably has impact on recruitment to an even greater extent compared to adult studies. In general, if a study is designed well, with a clear clinical question with which parents and children can identify, they are likely to consider participation. Open communication with all stakeholders involved will most likely result in ethically correct, practically feasible, scientifically sound, and economical reasonable studies to provide children with the appropriate treatment. From an academic perspective, feasibility, relevance, applicability and costs of clinical pharmacological studies in children can be signifi cantly improved by new sampling concepts(e.g., saliva, urine, dried spot blood) and the systematic introduction of already known information into the trial design through model based pediatric drug development, that mainly affect feasibility of pharmacokinetic studies. In contrast, for the pharmacodynamic part of pediatric studies, development and validation of population specifi c biomarkers or robust outcome variables is urgently needed.

Neonates need tailored drug formulations

Drugs are very strong tools used to improve outcome in neonates. Despite this fact and in contrast to tailored perfusion equipment, incubators or ventilators for neonates, we still commonly use drug formulations initially developed for adults. We would like to make the point that drug formulations given to neonates need to be tailored for this age group. Besides the obvious need to search for active compounds that take the pathophysiology of the newborn into account, this includes the dosage and formulation. The dosage or concentration should facilitate the administration of low amounts and be flexible since clearance is lower in neonates with additional extensive between-individual variability. Formulations need to be tailored for dosage variability in the low ranges and also to the clinical characteristics of neonates. A specific focus of interest during neonatal drug development therefore is a need to quantify and limit excipient exposure based on the available knowledge of their safety or toxicity. Until such tailored vials and formulations become available, compounding practices for drug formulations in neonates should be evaluated to guarantee the correct dosing, product stability and safety.

Clinical pharmacology of intravenous paracetamol in perinatal medicine

Clinical pharmacology aims to predict drug-related effects based on compound and population specific pharmacokinetics(PK, concentration-time), and pharmacodynamics(PD, concentration-effect). Consequently, dosing needs to be based on the physiological characteristics of the individual patient. Pregnancy and early infancy hereby warrant focused assessment. The specific characteristics of both subpopulations will be illustrated based on observations on intravenous(iv) paracetamol PK and PD collected in these specific populations. At delivery, there is a significant higher paracetamol clearance(+ 45%, L/h) when compared to non-pregnant observations. This higher clearance is in part explained by a proportional increase in oxidative metabolite production, but mainly an increase in glucuronidation. When focusing on PD, an association between maternal paracetamol exposure and atopy in infancy and fetal gastroshizis has been reported. In early infancy, paracetamol clearance is significantly lower and mainly depends on size(weight 0.75), while also the distribution volume is higher(L/kg). Reports on hepatic tolerance, haemodynamic stability and impact of bodytemperature have been published while the concentration effect profile for analgesia seems to be similar between neonates and children. Similar to maternal exposure, there are reports on the association with atopy. Studies on the use of paracetamol to close the patent ductus arteriosus are ongoing. At least, these observations provide evidence on the need to study commonly administered anesthetics in such specific subpopulations with specific focus on both population specific PK and PD to further improve patient tailored pharmacotherapy.