Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease
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Published on: March 14, 2017
Elsa Maksoud1, Berengere Koehl2,3, Aude Facchin1
1Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France.
Insights
This study optimized cefotaxime dosing for pediatric sickle cell disease (SCD) patients. A revised dose of 100 mg/kg every 6 hours is recommended to improve treatment effectiveness against bacterial infections in these vulnerable children.
Area of Science:
- Pharmacology and Therapeutics
- Pediatric Infectious Diseases
- Hematology
Background:
- Sickle cell disease (SCD) patients are susceptible to severe infections due to immune dysfunction.
- Cefotaxime is commonly used in pediatric SCD patients, but its pharmacokinetic profile in this population is not well-established.
- Understanding cefotaxime disposition is crucial for optimizing treatment in children with SCD.
Purpose of the Study:
- To determine the pharmacokinetic profile of cefotaxime in pediatric patients with SCD.
- To identify patient covariates influencing cefotaxime pharmacokinetics.
- To optimize cefotaxime dosage regimens using Monte Carlo simulations for improved therapeutic outcomes.
Main Methods:
- Population pharmacokinetic analysis of cefotaxime serum concentrations from 78 pediatric SCD patients.
- Development of a one-compartment pharmacokinetic model using NONMEM software.
- Monte Carlo simulations were performed to evaluate dosing strategies based on EUCAST MIC breakpoints.
Main Results:
- Cefotaxime pharmacokinetics in pediatric SCD patients were best described by a one-compartment model.
- Median weight-normalized volume of distribution was 0.42 L/kg and clearance was 0.38 L/h/kg.
- Cefotaxime clearance was significantly increased by 22% in patients with acute chest syndrome.
Conclusions:
- The study established cefotaxime pharmacokinetic parameters in pediatric SCD patients.
- Acute chest syndrome was identified as a covariate affecting cefotaxime clearance.
- A recommended cefotaxime dosage of 100 mg/kg every 6 hours is proposed to achieve therapeutic targets.
Abstract:
The pharmacokinetic profile of most drugs is dependent on the 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 hemolytic anemia, and a defective immunological function predisposing the individual to severe infection. Data on the impact of the disease on the disposition of cefotaxime are missing. In the present study, our aims were to determine cefotaxime pharmacokinetics when prescribed to children with SCD for suspected or proven bacterial infection, identify significant covariates, and perform Monte Carlo simulations to optimize the drug dosage. Cefotaxime serum concentrations were measured in 78 pediatric SCD patients receiving cefotaxime intravenously at a daily dose of 200 mg/kg of body weight 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 software and used for Monte Carlo simulations. Cefotaxime concentrations ranged from 0.05 to 103.7 mg/liter. Cefotaxime pharmacokinetics were best described by a one-compartment model: the median estimated weight-normalized volume of distribution and clearance were 0.42 liter/kg (range, 0.2 to 1.1 liter/kg) and 0.38 liter/h/kg (range, 0.1 to 1.2 liter/h/kg). Cefotaxime clearance increased by 22% in patients with acute chest syndrome. Dosing optimization, performed using EUCAST MIC susceptibility breakpoints, showed that a dose of 100 mg/kg/6 h should be used, depending on the patient's characteristics and clinical presentation, in order to reach a value of the percentage of time that the drug concentration exceeded the MIC under steady-state pharmacokinetic conditions of 80% in 80% of the patients when targeting sensitive Gram-positive cocci and Gram-negative bacilli with MICs of 1 mg/liter or below.
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