Study rationale

Dexamethasone is commonly used in paediatric intensive care units (PICUs) to prevent post-extubation stridor (PES), a potentially serious complication after endotracheal tube removal. However, dosing recommendations for dexamethasone in children vary significantly across guidelines in terms of the height of the dose, frequency of the dose and timing of the dose, though is applicable for the whole age range from 1 month to 18 years. This "one-size-fits-all" approach is illogical because dexamethasone metabolism varies greatly with age. The drug is metabolized by CYP3A4, an enzyme whose activity changes substantially during childhood, affecting plasma concentration and total drug exposure. This variation is not accounted for in current dosing recommendations. 

The role of PBPK modelling in supporting clinical decision-making

Physiologically-based pharmacokinetic (PBPK) modelling offers a solution by incorporating the age-related changes in drug metabolism, including the ontogeny of CYP3A4 activity. The model simulates how dexamethasone is processed across different paediatric age groups, allowing for tailored dosing recommendations. Since there is no established therapeutic concentration for PES prevention, a best-evidence target range was established by taking the best studied age group (i.e., 2–6 years) and the effective doses as a starting point. By adjusting doses based on age-specific drug metabolism, the model ensures that all age groups achieve comparable therapeutic exposure to dexamethasone.

Evaluation of paediatric dosing

PBPK modelling showed that a fixed regimen result in dexamethasone exposure variation across paediatric age groups. To match the target range observed in children aged 2–6 years, the data suggest dose reductions for neonates and older children. The reduced dosing in neonates was reflected in peadiactric dosing guidelines such as the Dutch peadiatric formulary (DPF), though not the reductions in older children. These adjustments are based on the known differences in CYP3A4 activity across the paediatric age span.

This study highlights the power of PBPK modelling in optimizing age-adjusted paediatric dosing by extrapolating the best available evidence. This approach ensures consistent therapeutic exposure across ages, addressing the limitations of weight-based dosing and improving both safety and efficacy for children.

The full paper can be accessed here.