Ceftaroline Dosage Optimized for Pediatric Patients With Renal Impairment Using Physiologically Based Pharmacokinetic Modeling.

Abstract

Ceftaroline fosamil is a fifth-generation cephalosporin approved as a treatment for adults and children with community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. However, its pharmacokinetics have not been fully evaluated in children with renal impairment. This study aimed to propose proper ceftaroline dosages optimized for the renally impaired pediatric population using physiologically based pharmacokinetic (PBPK) modeling. A PBPK model of ceftaroline was established and verified to simulate its disposition in the healthy population and renally impaired adults and to predict the exposure in renally impaired pediatric patients. Consistency was confirmed between simulated and observed data after intravenous administration of various ceftaroline regimens; fold errors were within the 2-fold error range. Among 6-year-old children, healthy subjects had 1.5-fold, 2-fold, and 2.6-fold lower areas under the plasma concentration-time curve (AUCs) than the moderate, severe, and end-stage renally impaired patient groups, respectively; among 1-year-old children, healthy subjects had 1.5-fold, 2.1-fold, and 2.5-fold lower AUCs than the respective renally impaired patient groups; among 1-month-old children, healthy subjects had 1.5-fold, 1.8-fold, and 2.2-fold lower AUCs than the respective renally impaired patient groups. The proposed dosage should be adjusted to 8, 6, and 5mg/kg every 8hours for patients aged ≥2 years to <18 years (≤33kg) with moderate, severe, and end-stage renal impairment, respectively; 5, 4, and 3mg/kg every 8hours for patients aged 2 months to <2 years with moderate, severe, and end-stage renal impairment, respectively; 4, 3.5, and 2.5mg/kg every 8hours for patients 0 to <2 months of age with moderate, severe, and end-stage renal impairment, respectively. Furthermore, pharmacodynamic investigations demonstrated that adequate antimicrobial effects were attained at the proposed doses in 3 age groups. Hence, our PBPK model can be an effective tool to support ceftaroline dosage proposals for renally impaired pediatric patients.