Population pharmacokinetics of cefotaxime and dosage recommendations in children with sickle cell disease. [PublishAheadOfPrint]

The pharmacokinetic profile of most drugs is dependent on patient's covariates and may be influenced by the disease. Cefotaxime is frequently prescribed in pediatric patients with sickle-cell disease (SCD), characterized by vaso-occlusive complications, chronic haemolytic anaemia and defective immunological function predisposing to severe infection. Data on the impact of the disease on cefotaxime disposition are missing. In the present study, our aims were to determine cefotaxime pharmacokinetics when prescribed in SCD children for suspected or proven bacterial infection, identify significant covariates and perform Monte-Carlo simulations to optimize drug dosage. Cefotaxime serum concentrations were measured in 78 pediatric SCD patients receiving cefotaxime intravenously at the daily dose of 200 mg/kg in three or four divided doses over 30 min. A total of 107 concentrations were available for pharmacokinetic analysis. A population pharmacokinetic model was developed with NONMEM and used for Monte-Carlo simulations. Cefotaxime concentrations ranged from 0.05 to 103.7 mg/l. Cefotaxime pharmacokinetics was best described by a one compartment model: The median (range) of estimated weight-normalized V and CL were 0.42 (0.2 to 1.1) l/kg and 0.38 (0.1 to 1.2) l/h/kg. Cefotaxime clearance increased by 22% in patients with acute chest syndrome. Dosing optimization, performed using EUCAST Minimum Inhibitory Concentration (MIC) susceptibility breakpoints, showed that the dose of 100 mg/kg/6h should be used, depending on patients' characteristics and clinical presentation, in order to reach a Time/MIC of 80% in 80% of patients when targeting sensitive Gram positive cocci and Gram negative bacilli with MICs of 1 mg/L or below.

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