Study rationale

Critically ill children in the paediatric intensive care units (PICU) often require prolonged opioid use, such as fentanyl or morphine. Abrupt discontinuation can lead to iatrogenic withdrawal syndrome (IWS), complicating recovery. A common approach is converting such short-acting opioids to methadone, a long-acting opioid, followed by gradual tapering. However, optimal conversion ratios and tapering strategies are unclear due to a lack of robust clinical evidence. In the absence of comparative clinical trials, a quantitative and mechanistic approach was needed to support decision-making.

The role of PBPK modelling in supporting clinical decision-making

PBPK model simulations of various opioid conversion ratios and tapering schedules served as clinical decision- support tool. The model simulated methadone exposure across different paediatric age groups to assess how age influences drug exposure. Also, Finally, different published tapering protocols were simulated to evaluate how methadone concentrations evolve over time during opioid tapering.

Evaluation of paediatric dosing

The simulations revealed that children aged 1–18 years had similar methadone exposure, while neonates had higher exposure due to immature drug clearance. Importantly, the 1–18-year age group with the lowest methadone exposure was used for further simulations to ensure that even those with higher clearance would achieve therapeutic drug levels. Simulations showed that a 1:10 conversion from fentanyl to methadone and a 1:1 conversion from morphine to methadone led to adequate methadone concentrations. Among the tapering protocols evaluated, the one strategy was selected which best maintained therapeutic methadone concentrations across various withdrawal risk categories. The definition of risk categories are defined by the number of days of opioid use, the total duration of the methadone tapering schedule, and the tapering steps themselves (single dose and dose frequency). The modelling results were then discussed with a multidisciplinary expert panel consisting of paediatric intensivists and hospital pharmacists. Based on both the simulation outcomes and clinical experience, consensus recommendations were formulated and implemented in the Dutch Paediatric Formulary.

PBPK modelling provided the best available evidence to rationally support opioid conversion and tapering recommendations in critically ill children, translating mechanistic pharmacology into practical clinical guidance. By visualizing drug concentrations during opioid conversion and tapering, PBPK modelling allowed clinicians to compare strategies in a transparent and reproducible way. The approach is ethically acceptable, avoids exposing vulnerable children to experimental dosing, and accelerates guideline development when traditional trials are not feasible.

The full, clinically endorsed recommendation should be obtained from Dutch Paediatric Formulary (Geneesmiddel | Methadon | Kinderformularium)