Non-maturational covariates for dynamic systems pharmacology models in neonates, infants, and children: Filling the gaps beyond developmental pharmacology.

Pharmacokinetics and -dynamics show important changes throughout childhood. Studies on the different maturational processes that influence developmental pharmacology have been used to create population PK/PD models that can yield individualized pediatric drug dosages. These models were subsequently translated to semi-physiologically or physiology-based PK (PBPK) models that support predictions in pediatric patient cohorts and other special populations. Although these translational efforts are crucial, these models should be further improved towards individual patient predictions by including knowledge on non-maturational covariates. These efforts are needed to ultimately get to systems pharmacology models for children. These models take developmental changes relating to the pediatric dynamical system into account but also other aspects that may be of importance such as abnormal body composition, pharmacogenetics, critical illness and inflammatory status.