Pharmacokinetics of meropenem in children receiving continuous renal replacement therapy: Validation of clinical trial simulations

Meropenem is frequently prescribed in critically ill children receiving continuous renal replacement therapy (CRRT). We previously used clinical trial simulations to evaluate dosing regimens of meropenem in this population and reported that a dose of 20 mg/kg every 12 hours optimizes target attainment. Meropenem pharmacokinetics were investigated in this prospective, open-label study to validate our previous in silico predictions. Seven patients received meropenem (13.8-22 mg/kg) administered intravenously every 12 hours as part of standard care. A mean dose of 18.6 mg/kg of meropenem was administered, resulting in a mean peak concentration of 80.1 mu g/mL. Meropenem volume of distribution was 0.35 +/- 0.085 L/kg. CRRT clearance was 40.2 +/- 6.6 mL/(min.1.73 m(2)) and accounted for 63.4% of the total clearance of 74.8 +/- 36.9 mL/(min.1.73 m(2)). Simulations demonstrated that a dose of 20 mg/kg every 12 hours resulted in a time above the minimum inhibitory concentration (% fT > MIC) of 100% in 5 out of 7 subjects, with a % fT > MIC of 93% and 43% in the remaining 2 subjects. We conclude that CRRT contributed significantly to the total clearance of meropenem. A dosing regimen of 20 mg/kg achieved good target attainment in critically ill children receiving CRRT, which is consistent with our previously published in silico predictions. Meropenem is a carbapenem antibiotic with broad-spectrum antimicrobial activity that is often used for empiric treatment of sepsis in the pediatric intensive care setting.[1] Sepsis is a frequent cause of acute kidney injury in children,[2, 3] which may require supportive care with continuous renal replacement therapy (CRRT). Critically ill patients requiring CRRT experience significant variability in drug disposition that may contribute to adverse clinical outcomes.[4, 5] Therefore, appropriate meropenem dosing recommendations are essential for children receiving CRRT, a population in whom mortality rates continue to exceed 40%.[6-8] Meropenem is primarily eliminated by the kidneys and therefore requires dosage adjustment in patients with renal impairment.[9, 10] The characteristics of meropenem, including its small molecular size, small volume of distribution, and insignificant protein binding, also render it extensively removed by CRRT. Pharmacokinetic profiles of meropenem in adult patients receiving CRRT have been investigated and shown extracorporeal removal ranging from 23% to 62% of the total clearance. These studies have recommended dosing regimens ranging from 500 mg to 1500 mg every 12 hours.[11-18] Meropenem, however, has not been studied in children receiving CRRT. We previously used clinical trial simulations to perform an in silico analysis of meropenem disposition in critically ill children receiving CRRT. Our results demonstrated that a dose of 20 mg/kg every 12 hours achieved acceptable target attainment in children older than 5 years of age.[19] This study is a prospective, open-label pharmacokinetic analysis of meropenem in critically ill children receiving CRRT. The purpose of this study was to (1) validate our previous pharmacokinetic model and in silico target attainment predictions and (2) develop appropriate dosing recommendations for this patient population.