Penetration of Ceftaroline into the Epithelial Lining Fluid of Healthy Adult Subjects

Abstract

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with bactericidal activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to (i) evaluate ceftaroline concentrations in human plasma and epithelial lining fluid (ELF) and (ii) develop a population pharmacokinetic (PK) model for plasma and ELF to be used in PK/pharmacodynamic (PD) target attainment simulations. Ceftaroline concentrations in ELF and plasma at steady state (day 4) were measured in healthy adult subjects for two dosages: 600 mg every 12 h (q12h) and 600 mg every 8 h (q8h). Both were well tolerated with no serious adverse events. The penetration of free ceftaroline into ELF, assuming 20% protein binding in plasma and no protein binding in ELF, was ≈23%. The population PK model utilized a two-compartment model for both ceftaroline fosamil and ceftaroline. Goodness-of-fit criteria revealed the model was consistent with observed data and no systematic bias remained. At 600 mg q12h and a MIC of 1 mg/liter, 98.1% of simulated patients would be expected to achieve a target free drug concentration above the MIC (fT>MIC) in plasma of 42%, and in ELF 81.7% would be expected to achieve a target fT>MIC of 17%; at 600 mg q8h, 100% were predicted to achieve an fT>MIC in plasma of 42% and 94.7% to achieve an fT>MIC of 17% in ELF. The literature and data suggest the 600 mg q12h dose is adequate for MICs of ≤1 mg/liter. There is a need for clinical data in patients with MRSA pneumonia and data to correlate PK/PD relationships in ELF with clinical outcomes.

FIG 1

Mean (± standard deviation) ceftaroline concentration versus time in plasma and epithelial lining fluid (ELF) of healthy subjects at steady state following the last dose of 600 mg ceftaroline fosamil q12h and q8h.

FIG 2

Observed versus population or individual predicted ceftaroline concentrations (milligrams per liter) in plasma and ELF. Values are indicated by black squares, and the line of identity appears as a solid black line.