Supporting clinical guidelines for opioid conversion to methadone and tapering to prevent withdrawal in critically ill children using physiology based pharmacokinetic modeling and simulation

Vollständiger Abstract

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Long-term opioid use is common in critically ill children and can cause withdrawal symptoms at discontinuation. To avoid withdrawal, short-acting opioids are usually converted into a long-acting drug, such as methadone, which is then carefully tapered. However, the exact conversion ratio and the optimal tapering protocol are unknown. This study aimed to design optimized conversion and tapering schedules of morphine and fentanyl to methadone for pediatric intensive care unit patients using physiologically-based pharmacokinetic (PBPK) modeling and expert panel decision-making. PBPK models of fentanyl, morphine, and methadone were verified with published pharmacokinetic data and opioid conversion ratios and relevant tapering protocols identified through literature review. Then, plasma concentration-time curves of opioid infusions (1 µg/kg/h fentanyl, 10 µg/kg/h morphine), several opioid-methadone conversion ratios, and different methadone tapering protocols were simulated. Predicted methadone plasma concentrations were compared to minimal therapeutic concentrations (i.e., 1 ng/mL for fentanyl, 4 ng/mL for morphine, and 60 ng/mL for methadone). These simulations were reviewed by the expert panel consisting of pediatric intensivists and hospital pharmacists to establish recommendations. Simulations showed that a conversion ratio of 1:10 for fentanyl and 1:1 for morphine resulted in therapeutic methadone concentrations. Most previously established tapering recommendations resulted in equal maximum methadone concentrations, except for the low-risk tapering schedules of two of the three protocols. The robustness of these findings is reinforced by both a target attainment analysis and a sensitivity analysis employing the therapeutic target of methadone. The panel established consensus-based Dutch recommendations for conversion and tapering. These findings demonstrate that PBPK models can support dosing decisions by simulating clinical scenarios. The resulting recommendations have been implemented in the Dutch Pediatric Formulary, ensuring that the model-informed recommendations are directly applied in clinical practice.