Population pharmacokinetic modeling and pharmacodynamic assessment of cefozopran in pediatric patients.

The aims of this study were to develop a population pharmacokinetic model for cefozopran in pediatric patients, and to use this model to evaluate the pharmacodynamics of cefozopran regimens against common bacterial populations. Plasma drug concentration data (110 samples from 31 pediatric patients) were modeled using the NONMEM program. The mean estimate and interindividual variance of the model were used in a Monte Carlo simulation to estimate the probabilities of attaining the bactericidal target for cefozopran (the time which the drug concentration remains above the minimum inhibitory concentration for the bacterium is 70% of the dosing interval). A two-compartment model fitted the data and body weight (BW, kg) was the most significant covariate. The final model was: Cl (l/h) = 0.674 x BW0.538, Vc (l) = 0.00233 x BW2.25 + 1.85, Q (l/h) = 1.46, and Vp (l) = 0.0964 x BW, where Cl is the clearance, Vc, and Vp are the volumes of distribution of the central and peripheral compartments, and Q is the intercompartmental clearance. The approved regimens of 20- or 40-mg/kg four times a day (0.5-h infusions), which were more effective than the corresponding three times a day-regimens, provided sufficient bactericidal effects on common bacterial populations (Escherichia coli, Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa) in most typical patients. These results better define the pharmacokinetics of cefozopran and help in the choice of appropriate regimens for pediatric patients.