Pharmacokinetics and Tolerability of Single-dose Intravenous Ertapenem in Infants, Children, and Adolescents

Abstract

Ertapenem is a carbapenem antibiotic with broad spectrum activity and a pharmacokinetic profile that favors once-daily administration in adults. This investigation was designed to evaluate the dose-exposure profile of ertapenem in children from infancy through adolescence. Eighty-four children (3 months-16 years) requiring antibiotic therapy were enrolled in this multicenter trial. Children received a single intravenous dose of ertapenem at 15, 20, or 40 mg/kg followed by repeated blood sampling for 24 hours. Free and total plasma ertapenem concentrations were quantitated by high-performance liquid chromatography, and the pharmacokinetics were determined using a model-independent approach. Ertapenem exposure increased proportionally with increasing dose; however, achievable concentrations were influenced by age. Children older than 12 years attained higher dose-normalized concentrations at the end of the infusion (concentration at the end of the infusion [Ceoi]: 8.7 ± 1.9 mg/L per mg/kg dose) and total body exposure (area under the curve area under the plasma concentration-time curve [AUC]0-∞: 34.7 ± 14.7 mg hr/L per mg/kg dose) as compared with children 2 to 12 years (Ceoi: 6.9 ± 2.4 mg/L per mg/kg dose, AUC0-∞: 18.4 ± 8.0 mg hr/L per mg/kg dose) and children younger than 2 years (Ceoi: 6.1 ± 2.2 mg/L per mg/kg dose, AUC0-∞: 17.0 ± 5.4 mg hr/L per mg/kg dose). These findings were accounted for by age-dependent changes in ertapenem clearance and distribution volume. In 3 children adverse events (nausea, n = 2; injection site reaction, n = 1) were considered related to study drug administration. Children younger than 12 years require dosing more frequently than once daily to achieve optimal efficacy when treating organisms with a minimum inhibitory concentration near the susceptibility breakpoint.