Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease

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.

Population pharmacokinetic models of first choice beta-lactam antibiotics for severe infections treatment: What antibiotic regimen to prescribe in children?

“…For amoxicillin, our review showed that the median clearance in the pediatric population are in accordance with previously reported values in critically ill adults (0.10 L/h/kg vs 0.13 L/kg) (63). Whereas for amoxicillin and cefotaxime, we observed a value of clearance divided by 2.0 for cefotaxime and 3.0 for ampicillin in the pediatric population (21,22,24,31,39,41,47,50). But if we looked at each amoxicillin studies in detail, we observed a large variability on amoxicillin clearance values as for piperacillin, explained by the same maturation process described previously (61) since numerous studies have been conducted in preterms and neonates (22,24,47,50).…”

Population Pharmacokinetic Estimates Suggest Elevated Clearance and Distribution Volume of Desethylamodiaquine in Pediatric Patients with Sickle Cell Disease Treated with Artesunate-Amodiaquine

“…Impaired hepatic and renal blood flow has been linked to elevated morphine clearance in SCD patients, 29 and to impaired lidocaine metabolism 30 . The large differences in clearance and volume of distribution is also consistent with the results of several studies that have shown differences in PK parameters between SCD and non-SCD populations for various drugs: the clearance of ciprofloxacin is reported to be 89% higher in SCD patients compared to non-SCD patients; 31 cefotaxime clearance has been shown to be higher in SCD patients, and higher still in SCD patients with acute chest syndrome; 32 and morphine clearance is reported to be 3-10 fold higher in SCD patients compared to published estimates in the non-SCD population 29 . The chronic inflammation in SCD may also induce drug metabolism, as demonstrated for codeine in SCD patients 33 .…”

The Exposome in Human Evolution: From Dust to Diesel

“…For malarial sickle cell disease, autopsies showed that nearly one-half of 300 had died of infections (Manci et al 2003). Effective treatments for sickle cell allele carriers (Maksoud et al 2018) will help maintain these and other adverse genes. Moreover, the expansion of neonatal intensive care units (NICUs) after 1950 has increased survival of low-birth weight babies (Drevenstedt et al 2008).…”