Meropenem in children receiving continuous renal replacement therapy: Clinical trial simulations using realistic covariates

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.

Pharmacokinetics of Continuous Infusion Meropenem With Concurrent Extracorporeal Life Support and Continuous Renal Replacement Therapy: A Case Report

“…[21][22][23][24][25][26][27] The standard meropenem dose in a patient this age is 20 mg/kg per dose IV every 8 to 12 hours. Further, Nehus et al 28 conducted clinical trial simulations to determine dosing regimens in children that would provide for a target attainment of 40% and 75% time above the MIC. Simulations suggested that a dosing regimen of 20 mg/kg per dose IV every 8 hours would be sufficient to obtain the aforementioned target attainments for children younger than 5 years.…”

Clinical Pharmacology Studies in Critically Ill Children

“…Additionally, some dialysis membranes can adsorb drugs in hemofiltration [97]. Previous studies have shown that the PK of meropenem and ticarcillin were altered in critically ill children supported with CRRT [99,100]. …”

“…Meropenem has also been studied in children with CRRT and ECMO [99,129]. Peak meropenem concentrations were decreased in children receiving CRRT with fluid overload by an average of 6.1% in patients with 10% fluid overload, 11.5% with 20% fluid overload, and 16% with 30% fluid overload [99]. However, fluid overload did not affect CL or the target attainment of 40% and 75% time above the minimum inhibitory concentration (4 mg/mL) [99].…”

“…Peak meropenem concentrations were decreased in children receiving CRRT with fluid overload by an average of 6.1% in patients with 10% fluid overload, 11.5% with 20% fluid overload, and 16% with 30% fluid overload [99]. However, fluid overload did not affect CL or the target attainment of 40% and 75% time above the minimum inhibitory concentration (4 mg/mL) [99]. In addition, a single case report in an 8 month old male infant on ECMO suggests that meropenem CL (4.14, 4.88, and 4.52 mL/kg/min on day 1 (8 h), day 3 (72 h), and day 9 (216 h), respectively) was slightly higher than estimates from healthy volunteers (4 mL/kg/min) [129].…”

In silico trials using Monte Carlo simulation to evaluate ciprofloxacin and levofloxacin dosing in critically ill patients receiving prolonged intermittent renal replacement therapy

“…For decades, in silico trials using Monte Carlo simulation (MCS) have been used to determine optimal drug regimens during drug discovery and development. This approach has been employed to predict optimal antibiotic doses in patients with IHD and CRRT [12,13], but not with PIRRT. Antibiotic dosing in patients with PIRRT is challenging, because dosing must take into account the pharmacokinetics altered not only by critical illness and but also by the timing of PIRRT and its associated drug clearance in relation to drug administration [14].…”