title: 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.
authors.affiliation: Forest Laboratories LLC, Jersey City, New Jersey, USA Todd.Riccobene@allergan.com.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Riccobene
authors.affiliation: Cerexa, Inc., Oakland, California, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Pushkin
authors.affiliation: Cerexa, Inc., Oakland, California, USA.
authors.forename: Alena
authors.initials: A
authors.lastname: Jandourek
authors.affiliation: Metrum Research Group LLC, Tariffville, Connecticut, USA.
authors.forename: William
authors.initials: W
authors.lastname: Knebel
authors.affiliation: Forest Laboratories LLC, Jersey City, New Jersey, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Khariton
mesh_terms: D000328:Adult; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology*; D002511:Cephalosporins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D000097583:Ceftaroline
chemical_list: D002511:Cephalosporins; D000097583:Ceftaroline