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.

A model-informed drug development approach was used to select ceftaroline fosamil high-dose regimens for pediatric patients with complicated skin and soft-tissue infection caused by Staphylococcus aureus with ceftaroline minimum inhibitory concentration (MIC) of 2 or 4 mg/L. Steady-state ceftaroline concentrations were simulated using a population 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 was calculated, based on patients achieving 35% fT>MIC (S. aureus PK/PD 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 q8h). 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 infusion q8h for patients >2 to 99% and ≥81% for MICs of 2 and 4 mg/L respectively) matched or exceeded adult predictions. Simulated Cmax,ss values were below maximum observed data in other indications, including a high-dose pediatric pneumonia trial, which reported no adverse events related to high exposure.