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Pharmacokinetics of Cefepime in Children on Extracorporeal Membrane Oxygenation: External Model Validation, Model
Céline Thibault1, Ganesh S Moorthy2,3, Christina Vedar3
1From the Department of Pediatrics, Division of Critical Care Medicine, CHU Sainte-Justine, Montreal, QC, Canada.
Insights
Cefepime dosing for children on extracorporeal membrane oxygenation requires optimization. An 8-hour interval is recommended for cefepime to achieve therapeutic drug concentrations against Gram-negative infections.
Area of Science:
- Pediatric Critical Care
- Pharmacokinetics and Pharmacodynamics
- Infectious Diseases
Background:
- Cefepime is a critical antibiotic for treating Gram-negative infections in pediatric patients requiring extracorporeal membrane oxygenation (ECMO).
- Established cefepime pharmacokinetic (PK) data in this vulnerable pediatric population is limited, necessitating further investigation for optimal dosing strategies.
Purpose of the Study:
- To establish a reliable population pharmacokinetic (PK) model for cefepime in pediatric patients undergoing ECMO.
- To determine optimal cefepime dosing regimens to achieve therapeutic drug exposure targets in this patient group.
Main Methods:
- A prospective, single-center PK study involving pediatric patients (<18 years) on ECMO receiving cefepime.
- External validation of a prior PK model followed by development of a revised, improved 2-compartment model using NONMEM with combined data.
- Dose-exposure simulations to identify optimal dosing based on maintaining free cefepime concentrations above the minimal inhibitory concentration (MIC).
Main Results:
- Initial model validation showed poor predictive performance.
- A revised 2-compartment PK model incorporated weight, serum creatinine, oxygenator day, and blood transfusion as covariates.
- A cefepime dosage of 50 mg/kg every 8 hours achieved target concentrations at an MIC of 8 mg/L.
Conclusions:
- An 8-hour dosing interval for cefepime is necessary to achieve adequate drug concentrations against Gram-negative infections with an MIC of 8 mg/L in pediatric ECMO patients.
- Adjusting dosing intervals based on serum creatinine levels and MIC values can further optimize cefepime therapy in this population.
Background:
Cefepime is a first-line therapy for Gram-negative infections in children on extracorporeal membrane oxygenation. Cefepime pharmacokinetics (PK) in children on extracorporeal membrane oxygenation still needs to be better established.
Methods:
This was a prospective single-center PK study. A maximum of 12 PK samples per patient were collected in children <18 years old on extracorporeal membrane oxygenation who received clinically indicated cefepime. External validation of a previously published population PK model was performed by applying the model in a new data set. The predictive performance of the model was determined by calculating prediction errors. Because of poor predictive performance, a revised model was developed using NONMEM and a combined data set that included data from both studies. Dose-exposure simulations were performed using the final model. Optimal dosing was judged based on the ability to maintain free cefepime concentrations above the minimal inhibitory concentration (MIC) for 68% and 100% of the dosing interval.
Results:
Seventeen children contributed 105 PK samples. The mean (95% CI) and median (interquartile range) prediction errors were 33.7% (19.8-47.7) and 17.5% (-22.6 to 74.4). A combined data set was created, which included 33 children contributing 310 PK samples. The final improved 2-compartment model included weight and serum creatinine on clearance and oxygenator day and blood transfusion on volume of the central compartment. At an MIC of 8 mg/L, 50 mg/kg/dose every 8 hours reached target concentrations.
Conclusions:
Dosing intervals of 8 hours were needed to reach adequate concentrations at an MIC of 8 mg/L. Longer dosing intervals were adequate with higher serum creatinine and lower MICs.
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