Model development and validation to improve pharmacotherapy in neonates

D rug therapy is important to improve the outcome of neonates. Despite this, paediatricians commonly still prescribe drugs developed for adults, extrapolating doses from to adult field of medicine and based on pathophysiology in adults. A powerful tool to improve neonatal pharmacotherapy and facilitate clinical studies is knowledge integration through pharmacokinetic (PK) modelling. PK modelling is through mechanism based PK or physiology-based (PB) PK. Mechanism based models apply a bottom-up ‘ from compound to model’ concept: based on drug specific observations, covariates are described, resulting in mechanism-based models. PB-PK applies a top-down ‘ from physiology to clinical observations’ concept: based on available data on neonatal physiology (e.g. weight, cardiac output, renal function), a PB-PK model is developed. Such models can guide study design and convert neonatal pharmacotherapy from explorative to confirmatory . The consecutive steps taken to model neonatal renal drug clearance illustrate the feasibility of such an approach. Besides clinical relevance, the same observations also unveil maturational patterns, and guide research on gaps in the knowledge on developmental physiology. This will be illustrated based on cefazolin (maturation of renal tubular transport) and propylene glycol (hepatic compared to renal elimination) clearance.