Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease
Authors: Koehl Bérengère , Maksoud Elsa , Ha Phuong , Zhao Wei , Kaguelidou Florentia , Benkerrou Malika , Mariani Patricia , Lorrot Mathie , Faye Albert , Jacqz-Aigrain Evelyne , Baruchel Andre 
Published: April 2021

Abstract

Background: The pharmacokinetic profile of most drugs is dependent on patient's covariates and may be influenced by the disease. Cefotaxime is frequently prescribed in paediatric patients with Sickle Cell Disease (SCD), characterized by vaso-occlusive complications, chronic haemolytic anaemia and defective immunological function predisposing to severe infection. Considering the very particular inflammatory context and the complexity of the disease, one may suspect than SCD could influence the pharmacokinetic profile of many drugs, which has already been reported for the morphine in SCD patients. Data on the impact of SCD on Cefotaxime disposition are missing, while the prescription of an optimal treatment against potentially fatal infections is essential. 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.
Results: Cefotaxime serum concentrations were measured in 80 paediatric SCD patients receiving Cefotaxime. A total of 110 concentrations were available for pharmacokinetic analysis. The population pharmacokinetic model developed from the SCD samples analyze made it possible to predict the plasma concentrations obtained according to the prescribed dosages.
We found that the prescription of a standard dose of Cefotaxime (50 mg/kg every 8 hours) or a high dose of Cefotaxime (50 mg/kg every 6 hours) were both insufficient to reach the therapeutic target (ie a time above the minimum inhibitory concentration of the germ (T&gt;MIC) of 80%, which is recommended for severe bacterial infection), particularly in young children (Figure 1) . With the standard dose of Cefotaxime, only 38% of patients under 12 years old reached the therapeutic target, which increase to 82% with a high dose, meaning that 18% of the patients are still not efficiently treated in case of bacteria infection. In case of germs (Streptococcus pneumoniae or Salmonella) with intermediate sensitivity (MCI=1g/l), the amount of underdosed patients could reach 81% with the prescription of a standard dose (Figure 1).
Moreover, Cefotaxime clearance increased by 22% in patients with acute chest syndrome, highlighting the possible impact of severe vaso-occlusion and inflammation on drug metabolism.
Conclusion: Our data suggest that SCD patients, particularly young children, may have a particular Cefotaxime pharmacokinetic profile, possibly due to severe inflammatory condition. Considering the predisposition to severe infection in these patients, the prescribed dose of Cefotaxime should not be lower than 50 mg/kg/6h. In case of acute chest syndrome, this dose could even be insufficient to treat a bacterial infection (including due to sensitive germ with MIC= 0.5g/L or below) and should be adapted depending on patients' characteristics and clinical presentation.

Disclosures
No relevant conflicts of interest to declare.