The use of extrapolation based on modeling and simulation to support high‐dose regimens of ceftaroline fosamil in pediatric patients with complicated skin and soft‐tissue infections

Abstract

Abstract A model‐informed drug development approach was used to select ceftaroline fosamil high‐dose regimens for pediatric patients with complicated skin and soft‐tissue infections caused by Staphylococcus aureus with a ceftaroline minimum inhibitory concentration (MIC) of 2 or 4 mg/L. Steady‐state ceftaroline concentrations were simulated using a population pharmacokinetics (PK) model for ceftaroline fosamil and ceftaroline including data from 304 pediatric subjects and 944 adults. Probability of target attainment (PTA) for various simulated pediatric high‐dose regimens and renal function categories were calculated based on patients achieving 35% fT>MIC (S. aureus PK/pharmacodynamic target for 2‐log10 bacterial killing). For extrapolation of efficacy, simulated exposures and PTA were compared to adults with normal renal function receiving high‐dose ceftaroline fosamil (600 mg 2‐h infusions every 8 h). For safety, predicted ceftaroline exposures were compared with observed pediatric and adult data. Predicted ceftaroline exposures for the approved pediatric high‐dose regimens (12, 10, or 8 mg/kg by 2‐h infusions every 8 h for patients aged >2 to 99% and ≥81% for MICs of 2 and 4 mg/L, respectively) matched or exceeded the adult predictions. Simulated Cmax,ss values were below the maximum observed data in other indications, including a high‐dose pediatric pneumonia trial, which reported no adverse events related to high exposure.