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Phenobarbital in intensive care unit pediatric population: predictive performances of population pharmacokinetic
Amélie Marsot1, Fabrice Michel2, Estelle Chasseloup1
1Service de Pharmacologie Clinique et Pharmacovigilance, Pharmacologie Intégrée et Interface Clinique Industrielle, Institut des Neurosciences Timone - AMU-CNRS 7289, Aix-Marseille Université, AP-HM, Hopital Timone - Bâtiment F, 264 rue Saint Pierre, Marseille, 13385, France.
Insights
This study validated a phenobarbital population pharmacokinetic model for pediatric intensive care units. The model accurately predicts drug concentrations, supporting optimized dosing regimens for critically ill children.
Area of Science:
- Pharmacology
- Pediatric Critical Care
- Pharmacokinetics
Background:
- Phenobarbital dosing requires accurate pharmacokinetic models, especially in pediatric intensive care units (PICUs).
- External validation of existing models is crucial for confirming their applicability and extending recommendations to broader patient populations.
- The Marsot et al. model for phenobarbital pharmacokinetics in neonates needs evaluation in a diverse PICU population.
Purpose of the Study:
- To externally evaluate the phenobarbital population pharmacokinetic model by Marsot et al. in a pediatric intensive care unit setting.
- To confirm the model's predictive performance and assess its suitability for dose adjustment in critically ill children.
- To extend the validated dosing recommendations to the entire PICU population.
Main Methods:
- Retrospective analysis of phenobarbital concentrations from 35 pediatric intensive care unit patients.
- Implementation of the Marsot et al. population pharmacokinetic model using NONMEM 7.3 software.
- Assessment of predictive performance using bias, inaccuracy, Normalized Prediction Distribution Errors (NPDE), and Visual Predictive Check (VPC).
Main Results:
- The model demonstrated reasonable bias and inaccuracy in predicting phenobarbital concentrations.
- Median prediction error was 3.03% and median absolute prediction error was 26.20%.
- No significant trends were observed in NPDE and VPC, indicating good model performance.
Conclusions:
- The phenobarbital population pharmacokinetic model by Marsot et al. is externally validated for IV infusion administration in a PICU setting.
- The model-based dosing regimen can be extended to optimize phenobarbital treatment in all PICU patients.
- Therapeutic drug monitoring is recommended alongside the model-based dosing due to inter- and intra-patient variability.
Abstract:
An external evaluation of phenobarbital population pharmacokinetic model described by Marsot et al. was performed in pediatric intensive care unit. Model evaluation is an important issue for dose adjustment. This external evaluation should allow confirming the proposed dosage adaptation and extending these recommendations to the entire intensive care pediatric population. External evaluation of phenobarbital published population pharmacokinetic model of Marsot et al. was realized in a new retrospective dataset of 35 patients hospitalized in a pediatric intensive care unit. The published population pharmacokinetic model was implemented in nonmem 7.3. Predictive performance was assessed by quantifying bias and inaccuracy of model prediction. Normalized prediction distribution errors (NPDE) and visual predictive check (VPC) were also evaluated. A total of 35 infants were studied with a mean age of 33.5 weeks (range: 12 days-16 years) and a mean weight of 12.6 kg (range: 2.7-70.0 kg). The model predicted the observed phenobarbital concentrations with a reasonable bias and inaccuracy. The median prediction error was 3.03% (95% CI: -8.52 to 58.12%), and the median absolute prediction error was 26.20% (95% CI: 13.07-75.59%). No trends in NPDE and VPC were observed. The model previously proposed by Marsot et al. in neonates hospitalized in intensive care unit was externally validated for IV infusion administration. The model-based dosing regimen was extended in all pediatric intensive care unit to optimize treatment. Due to inter- and intravariability in pharmacokinetic model, this dosing regimen should be combined with therapeutic drug monitoring.