Study rationale 

Carbamazepine and valproic acid (VPA) are long-established treatments for paediatric epilepsy. However, their dosing presents challenges due to their complex pharmacokinetics, especially in children. Both drugs also exhibit high inter-individual variability. VPA is extensively bound to albumin, while carbamazepine undergoes auto-induction, both of which complicate dose optimization. This study aimed to evaluate the current Dutch Paediatric Formulary (DPF) dosing guidelines for carbamazepine and VPA and provide insight into how altered albumin levels impact VPA exposure.

The role of PBPK modelling in supporting clinical decision-making

PBPK modelling takes the body’s physiological processes into account, providing a more comprehensive understanding of how drugs behave across different age groups. In this study, PBPK models for carbamazepine and VPA were used to simulate paediatric drug levels under current dosing guidelines. These models helped evaluate whether existing guidelines were adequate for achieving therapeutic drug levels in children and provided deeper insights into how factors like hypoalbuminemia affect VPA dosing.

Evaluation of paediatric dosing

The simulations showed that therapeutic levels of both drugs were expected to be reached within 1 to 2 weeks of treatment, confirming the appropriateness of the current DPF dosing guidelines for most paediatric age groups. However, the modelling also highlighted specific age groups where optimisation was advisable. For neonates and children aged 12-18, a higher starting dose of carbamazepine was recommended to reach therapeutic levels more quickly, considering the increased metabolic clearance in this age groups. Additionally, PBPK modelling provided valuable mechanistic insights into metabolite exposure, enzyme maturation, and the impact of protein binding, particularly the effect of hypoalbuminemia on VPA exposure. Based on these findings, the study recommends routinely assessing unbound VPA levels when high doses are required or in cases of reduced albumin levels.

PBPK modelling proved to be a valuable tool to evaluate current dosing guidelines, and how it can support clinical decision-making.