Pharmacokinetic and Pharmacodynamic Target Attainment in Adult and Pediatric Patients Following Administration of Ceftaroline Fosamil as a 5‐Minute Infusion

Abstract

The key pharmacokinetic/pharmacodynamic (PK/PD) efficacy index for β‐lactam antibiotics is the percentage of time that free drug concentrations exceed the minimum inhibitory concentration (MIC) of bacteria during each dosing interval (fT>MIC). Ceftaroline fosamil, the prodrug of the β‐lactam ceftaroline, was initially approved for administration as 60‐minute intravenous (IV) infusions. Population PK analyses comparing exposure and PK/PD target attainment for 5‐minute and 60‐minute IV infusions, described here, have supported ceftaroline fosamil labeling updates to include variable infusion durations of 5 to 60 minutes in adults and children aged ≥2 months. A 2‐compartment disposition PK model for ceftaroline fosamil and ceftaroline was used to predict steady‐state ceftaroline exposures (maximum plasma concentrations [Cmax,ss] and area under the plasma concentration–time curve over 24 hours [AUCss,0‐24]) and probability of target attainment in simulated adult and pediatric patients with various degrees of renal function receiving standard doses of ceftaroline fosamil as 5‐minute or 60‐minute IV infusions. Across age groups and renal function categories, median ceftaroline AUCss,0‐24 values were similar for 5‐minute and 60‐minute infusions, whereas Cmax,ss was up to 42% higher for 5‐minute infusions. Both infusion durations achieved >99% probability of target attainment based on PK/PD targets for Staphylococcus aureus (35% fT>MIC) and Streptococcus pneumoniae (44% fT>MIC) at European Committee on Antimicrobial Susceptibility Testing/Clinical and Laboratory Standards Institute MIC breakpoints (1 mg/L and 0.25/0.5 mg/L, respectively). These findings support administration of standard ceftaroline fosamil doses over 5 to 60 minutes for adults and children aged ≥2 months, providing added flexibility to clinicians and patients.

Ceftaroline Fosamil for Treatment of Pediatric Complicated Skin and Soft Tissue Infections and Community-Acquired Pneumonia

“…Since it can be challenging to conduct large-scale efficacy trials in pediatric populations, extrapolation approaches combining observed PK and safety data in children with adult efficacy and safety data and population PK modeling/simulation and PTA analysis are accepted techniques to support antibiotic dose selection and approval in pediatric drug development [ 56 – 59 ]. Using the updated PK/PD targets described above, population PK modeling and simulations have shown that standard ceftaroline fosamil adult and pediatric doses provide high (> 90%) PTA across all age groups against target pathogens at their respective EUCAST and CLSI susceptible MIC breakpoints [ 53 , 60 ].…”

“…The addition of pediatric dosing recommendations in the European and US labels was based on completion of the PIP and fulfillment of PREA requirements, which included clinical trials in relevant pediatric indications and population PK analyses [ 60 , 65 ]. In the case of the European label, the pediatric population PK analyses used the PK/PD targets described by Das et al [ 53 ], with these analyses demonstrating drug exposures and PTA in pediatric patients equivalent to adults with normal renal function receiving standard and high ceftaroline fosamil doses.…”

“…A population PK model was used to predict ceftaroline exposure metrics and conduct PTA simulations following ceftaroline fosamil IV infusion durations of 5 or 60 min for patients across a range of age and renal function groups [ 52 , 60 ]. Ceftaroline fosamil standard doses (Supplementary Table S2, see ESM) administered by 5-min and 60-min IV infusions achieved similar PTA (≥ 99%) against S. aureus and S. pneumoniae at their respective PK/PD targets at EUCAST/CLSI MIC susceptibility breakpoints in all simulated age groups [ 60 ]. These analyses supported the inclusion in European and US labeling of variable infusion times of 5–60 min for standard ceftaroline fosamil doses in adults and children aged ≥ 2 months [ 7 , 8 ].…”

Efficacy of ceftaroline and rifampin, alone or combined, in a rat model of methicillin-resistant Staphylococcus epidermidis osteomyelitis without implant

“…After 12 h post-injection, ceftaroline was eliminated from the blood compartment, and the area under the concentration-time curve from 0 to 24 h (AUC 0–24 ) was 49.5 µg.h/mL (considering a twice daily regimen was applied). Thus, the C max achieved in the rat was similar to the C max reported in humans (20.8 µg/mL on average following a 600 mg/12 h administration)( 24 ) but the AUC in the rat was approximately half the AUC obtained in humans (97.5 µg.h/mL on average), and the % T >MIC was, therefore, about 40% in the rat, based on an MIC of 0.5 µg/mL for the MRSE strain used in this study ( 25 ).…”

Quantification of Ceftaroline in Human Plasma Using High-Performance Liquid Chromatography with Ultraviolet Detection: Application to Pharmacokinetic Studies

“…Ceftaroline clearance is significantly affected by age, renal function or the presence of infection [ 14 ]. As a beta-lactam antimicrobial, the pharmacokinetic/pharmacodynamic (PK/PD) index that better correlates with efficacy is the time, expressed as the percentage of the dosing interval by which free drug concentration is over the minimum inhibitory concentration (MIC) of the bacteria responsible for the infection (% f T >MIC ) [ 15 , 16 ].…”