Individualized dosing regimens in children based on population PKPD modelling: are we ready for it?

Abstract

Despite profound differences in response between children and adults, and between children of different ages, drugs are still empirically dosed in mg/kg in children. Since maturation of expression and function is typically a non-linear dynamic process which differs between biotransformation routes and pharmacological targets, paediatric dosing regimens should be based on the changing pharmacokinetic-pharmacodynamic (PKPD) relationship in children. In this respect, the population approach is essential, allowing for sparse sampling in each individual child. An example is presented on morphine glucuronidation, for which two covariates were identified and subsequently used to derive a model-based dosing algorithm for a prospective clinical trial in children. Using this novel dosing algorithm, similar morphine concentrations are expected while, depending on age, lower and higher morphine dosages are administered compared to mg/kg/h dosing. As the covariate functions may reflect system-specific information on the maturation of a specific drug-disposition pathway, its use for other drugs that share the same pathway is explored. For this purpose, prospective clinical trials and cross-validation studies are urgently needed. In conclusion, PKPD modelling and simulation studies are important to develop evidence-based and individualized dosing schemes for children, with the ultimate goal to improve drug safety and efficacy in this population.