A Critical Review on the Clinical Pharmacokinetics, Pharmacodynamics, and Clinical Trials of Ceftaroline

Only a parenteral formulation of ceftaroline is commercially available, and the prodrug, ceftaroline fosamil, is hydrolyzed quickly and completely upon intravenous administration. Ceftaroline is relatively minimally bound to plasma proteins (15-28 %), with a volume of distribution of 30-40 L. Ceftaroline undergoes minimal metabolism and does not appear to be a cytochrome P450 substrate. Its renal clearance (e.g. 4-7 L/h after multiple dosing) approximates glomerular filtration rate, with a terminal half-life of similar to 2.6 h in healthy subjects. The pharmacokinetics of ceftaroline have been described thoroughly in clinical investigations primarily conducted by the manufacturer. Despite its indications for treating skin and skin structure infections (SSSI) or community-acquired pneumonia (CAP), some studies that contributed data to the final drug labelling were conducted only in healthy volunteers. A significant amount of data have been contributed by the drug maker, and the overall quality of the pharmacodynamics and clinical data, based on our critical analysis provided in this review, is strong. Ceftaroline can be considered as a therapeutic alternative for complicated SSSI and CAP (Pneumonia Outcome Research Team Class III-IV). The current dosing regimen of ceftaroline 600 mg intravenously every 12 h appears sufficient to establish pharmacokinetic-pharmacodynamic relationships and achieve optimal clinical efficacy. More clinical studies are needed to define the place of ceftaroline in therapy for SSSI, CAP, and other indications such as osteomyelitis, endocarditis, and other types of pneumonia. Moreover, continued development in population modelling incorporating more patient-specific data would allow further analysis to identify intrinsic and extrinsic factors that influence the pharmacokinetics of ceftaroline in humans.