Population Pharmacokinetic Model to Optimize Cefotaxime Dosing Regimen in Critically Ill Children

Agathe Béranger, Mehdi Oualha, Saïk Urien, Mathieu Genuini, Sylvain Renolleau, Radia Aboura, Déborah Hirt, Claire Heilbronner, Julie Toubiana, Jean-Marc Tréluyer, Sihem Benaboud

During sepsis, optimal plasma antibiotic concentrations are mandatory. Modifications of pharmacokinetic parameters could lead to low drug concentrations and therefore, insufficient therapeutic levels. The aim of this study was to build a population pharmacokinetic model for cefotaxime and its metabolite desacetylcefotaxime in order to optimize individual dosing regimens for critically ill children. All children aged < 18 years, weighing more than 2.5 kg, and receiving intermittent cefotaxime infusions were included in this study. Cefotaxime and desacetylcefotaxime were quantified by high-performance liquid chromatography. Pharmacokinetics were described using the non-linear mixed-effect modeling software MONOLIX, and Monte Carlo simulations were used to optimize dosing regimen in order to maintain serum concentrations above the target concentration (defined at 2 mg·L(-1)) throughout the dosing interval. We included 49 children with a median (range) postnatal age of 23.7 (0.2-229) months, and median body weight (range) of 10.9 (2.5-68) kg. A one-compartment model with first-order elimination adequately described the data. Median (range) values for cefotaxime clearance, desacetylcefotaxime clearance, and volume of distribution were 0.97 (0.3-7.1) L·h(-1), 3.2 (0.6-16.3) L·h(-1), and 0.3 (0.2-0.41) L·kg(-1), respectively. Body weight and postnatal age were statistically significant covariates. Cefotaxime-calculated residual concentrations were low, and no patient succeeded in attaining the target. Unlike intermittent administration, a dosing regimen of 100 mg·kg(-1)·day(-1) administered by continuous infusion provided a probability of target attainment of 100%, regardless of age and weight. Standard intermittent cefotaxime dosing regimens in critically ill children are not adequate to reach the target. We showed that, for the same daily dose, continuous infusion was the only administration that enabled the target to be attained, for children over 1 month of age. As continuous administration is achievable in the pediatric intensive care unit, it should be considered for clinical practice. Registered at http://www.clinicaltrials.gov , NCT02539407.