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Meropenem in children receiving continuous renal replacement therapy: clinical trial simulations using realistic
Edward J Nehus1, Samer Mouksassi, Alexander A Vinks
1Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio.
Insights
Optimizing meropenem dosing for children on continuous renal replacement therapy (CRRT) is crucial. Dosing adjustments are needed for younger children, but fluid overload did not impact meropenem target attainment.
Area of Science:
- Pediatric Nephrology
- Pharmacokinetics
- Infectious Diseases
Background:
- Meropenem is commonly used in pediatric patients undergoing continuous renal replacement therapy (CRRT).
- Critically ill children often experience fluid overload, potentially altering drug disposition.
- Optimizing meropenem dosing is essential for effective treatment against pathogens like P. aeruginosa.
Purpose of the Study:
- To develop a pharmacokinetic model for meropenem in children on CRRT.
- To evaluate meropenem dosing regimens for target attainment against P. aeruginosa.
- To assess the impact of fluid overload on meropenem target attainment.
Main Methods:
- Utilized clinical trial simulations based on published pharmacokinetic parameters.
- Incorporated data from 287 pediatric patients from a CRRT registry, including weight and fluid overload.
- Evaluated target attainment based on 40% and 75% time above the minimum inhibitory concentration.
Main Results:
- Children over 5 years achieved target attainment with 20 mg/kg every 12 hours.
- Children under 5 required a higher dose of 20 mg/kg every 8 hours for optimal target attainment.
- Fluid overload did not significantly affect meropenem target attainment in the simulated population.
Conclusions:
- Meropenem dosing requires age-specific adjustments in pediatric CRRT patients.
- Current simulations suggest fluid overload does not necessitate dosing changes.
- In vivo validation is required to confirm these in silico findings for meropenem therapy.
Abstract:
Meropenem is frequently prescribed in children receiving continuous renal replacement therapy (CRRT). Fluid overload is often present in critically ill children and affects drug disposition. The purpose of this study was to develop a pharmacokinetic model to (1) evaluate target attainment of meropenem dosing regimens against P. aeruginosa in children receiving CRRT and (2) estimate the effect of fluid overload on target attainment. Clinical trial simulations were employed to evaluate target attainment of meropenem in various age groups and degrees of fluid overload in children receiving CRRT. Pharmacokinetic parameters were extracted from published literature, and 287 patients from the prospective pediatric CRRT registry database provided realistic clinical covariates including patient weight, fluid overload, and CRRT prescription characteristics. Target attainment at 40% and 75% time above the minimum inhibitory concentration was evaluated. Clinical trial simulations demonstrated that children greater than 5 years of age achieved acceptable target attainment with a dosing regimen of 20 mg/kg every 12 hours. In children less than 5, however, increased dosing of 20 mg/kg every 8 hours was needed to optimize target attainment. Fluid overload did not affect target attainment. These in silico model predictions will need to be verified in vivo in children receiving meropenem and CRRT.
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