Drug disposition and clinical practice in neonates: cross talk between developmental physiology and pharmacology

Abstract

Drug dosing in infants should be based on their physiological characteristics and the pharmacokinetic and -dynamic profile of the compound. Since maturational physiological changes are most prominent in infancy, variability is the key feature of clinical pharmacology in infancy: developmental physiology drives developmental pharmacology. This is illustrated by the link between renal physiology and renal drug clearance and between hepatic physiology and hepatic drug elimination for some specific compounds. However, the maturational profiles of the individual elimination processes differ substantially at the enzyme and transporter level. This implies that it is important to integrate all ontogeny-related knowledge of the different elimination routes to predict compound specific, phenotypic in vivo observations of infancy. In addition to the introduction of already available in vivo observations to validate mechanistic (estimated to in vivo observations) or physiology based pharmacokinetic (PBPK, developmental physiology related estimated to in vivo observations) models, a simultaneous use of both approaches (mechanistic and PBPK) to search for discrepancies between both approaches may also unveil 'missing' links in maturational physiology or clinical pharmacology (e.g. ontogeny renal or hepatic drug transporters): developmental pharmacology drives developmental pharmacology.