Optimal Dosing of Ceftriaxone in Infants Based on a Developmental Population Pharmacokinetic-Pharmacodynamic Analysis.

ABSTRACT

Ceftriaxone is a third-generation cephalosporin used to treat infants with community-acquired pneumonia. Currently, there is a large variability in the amount of ceftriaxone used for this purpose in this particular age group, and an evidence-based optimal dose is still unavailable. Therefore, we investigated the population pharmacokinetics of ceftriaxone in infants and performed a developmental pharmacokinetic-pharmacodynamic analysis to determine the optimal dose of ceftriaxone for the treatment of infants with community-acquired pneumonia. A prospective, open-label pharmacokinetic study of ceftriaxone was conducted in infants (between 1 month and 2 years of age), adopting an opportunistic sampling strategy to collect blood samples and applying high-performance liquid chromatography to quantify ceftriaxone concentrations. Developmental population pharmacokinetic-pharmacodynamic analysis was conducted using nonlinear mixed effects modeling (NONMEM) software. Sixty-six infants were included, and 169 samples were available for pharmacokinetic analysis. A one-compartment model with first-order elimination matched the data best. Covariate analysis elucidated that age and weight significantly affected ceftriaxone pharmacokinetics. According to the results of a Monte Carlo simulation, with a pharmacokinetic-pharmacodynamic target of a free drug concentration above the MIC during 70% of the dosing interval (70% fT>MIC), regimens of 20 mg/kg of body weight twice daily for infants under 1 year of age and 30 mg/kg twice daily for those older than 1 year of age were suggested. The population pharmacokinetics of ceftriaxone were established in infants, and evidence-based dosing regimens for community-acquired pneumonia were suggested based on developmental pharmacokinetics-pharmacodynamics.