Artikel
Plasma and soft tissue pharmacokinetics of ceftaroline after single and repeated administration of two dosing regimens of ceftaroline fosamil – a microdialysis study in healthy volunteers
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Autoren
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P. Matzneller
- Medizinische Universität Wien Universitätsklinik für Klinische Pharmakologie – Wien, Österreich
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E. Lackner
- Medizinische Universität Wien Universitätsklinik für Klinische Pharmakologie – Wien, Österreich
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P. Severin
- COVANCE Laboratories Inc Bioanalytical Chemistry – Madison, USA
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M. Zeitlinger
- Medizinische Universität Wien Universitätsklinik für Klinische Pharmakologie – Wien, Österreich
| Veröffentlicht: | 25. September 2014 |
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Gliederung
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Aim: Ceftaroline fosamil is currently approved for treatment of complicated skin and soft tissue infections and community-acquired pneumonia at a dosage of 600 mg twice daily (bid), but other dosing regimens are under evaluation. Soft tissue pharmacokinetics (PK) of the active compound ceftaroline has not been described yet. In the present study, PK of ceftaroline in plasma and soft tissues of healthy volunteers was determined by microdialysis for two different dosing regimens of ceftaroline fosamil.
Method: Ceftaroline concentrations in plasma, muscle and subcutaneous adipose tissue of n=12 male healthy volunteers were measured by microdialysis after single and repeated intravenous administration of 600 mg ceftaroline fosamil bid or three times daily (tid) to two groups of n=6 subjects each. Duration of ceftaroline fosamil infusion was 1 hour in the bid group and 2 hours in the tid group. Relevant PK and pharmacokinetic/pharmacodynamic (PK/PD) parameters were calculated and compared between groups.
Results: Ceftaroline fosamil was generally well tolerated. Single and repeated dose concentration-time profiles of ceftaroline in plasma, muscle and subcutis of volunteers of both study groups are shown in Figure 1 [Fig. 1]. In plasma, Cmax, AUC0-24 and %T>MIC of ceftaroline for the currently established threshold of 1 mg/L were significantly higher in the tid group. In analogy, relevant PK parameters in soft tissues were descriptively higher in the tid group, although high inter-individual variability was observed. Assuming a plasma protein binding of 20%, ratios between AUC0-n of free ceftaroline in soft tissues and AUC0-n of calculated free fraction in plasma ranged from 0.48 to 0.98 for muscle and from 0.47 to 0.83 in subcutis, respectively.
Conclusion: Present data have shown that ceftaroline fosamil tid leads to higher and prolonged ceftaroline exposure in plasma and soft tissues of healthy volunteers, and would therefore support the administration of this drug with a shorter dosage interval.
Financial disclosure: This study was partly funded by AstraZeneca.
