title: 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.
authors.affiliation: Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Nehus
authors.forename: Samer
authors.initials: S
authors.lastname: Mouksassi
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
authors.forename: Stuart
authors.initials: S
authors.lastname: Goldstein
mesh_terms: D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D006801:Humans; D007223:Infant; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D017582:Renal Replacement Therapy; D013845:Thienamycins / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem
keywords: continuous renal replacement therapy; meropenem; pediatrics; pharmacokinetics