Pharmacokinetics of Cefepime in Children on Extracorporeal Membrane Oxygenation

Abstract

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 NON-MEM and a combined data set that included data from both studies. Doseexposure 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.

Pharmacokinetic Research in Pediatric Extracorporeal Therapies: Current State and Future Directions

“…Careful pre-study planning to precisely define the study's goals while considering ethical aspects in a population where limited phlebotomies may be allowed is key. Finally, accounting for ECLS circuit age is important as the degree to which they alter PK parameters may change over time [32][33][34]. This may be due to saturable adsorption of drugs within the circuit elements, a wellknown issue in ECMO that has also been demonstrated for clinically relevant drugs in CRRT [13], as well as the formation of proteinaceous second membranes on the CRRT filter itself which limits solute clearance [32].…”