Individualization of Cefuroxime Dosage using Pharmacodynamic targets, MIC distributions and Minimization of a Risk Function
Viberg, Anders (1), Otto Cars (2), Mats O. Karlsson (1) and Siv Jönsson (3)
(1) Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (2)Department of Medical Sciences, Infectious Disease, Uppsala University Hospital, Uppsala, Sweden (3) AstraZeneca R&D, Södertälje, Sweden
Objectives: When developing drug dosing strategies, benefits and disadvantages of treatment are balanced. For cephalosporins, such as cefuroxime, the aim from an efficacy viewpoint is exposing patients to concentrations above the minimum inhibitory concentration (MIC) for at least 50 % of the dosing interval. Preferably, the amount of drug administered in excess to reach target should be minimized. Further, the duration of continuous time below MIC may be of importance for outcome. By minimizing a multi-dimensional risk function, those aspects were considered when establishing dosing strategies for cefuroxime individualized on creatinine clearance.
Methods: The aim and risk function for cefuroxime treatment were defined by weighing the time of cefuroxime exposure above, and below, MIC per dosing interval and the amount of drug given. The population to be treated was described by a population pharmacokinetic model (1) for cefuroxime and empirical distributions of relevant covariates. Dosing strategies were estimated in which the MIC was fixed to 0.25, 1, 8 or 16 mg/L. The estimated dosing strategies were assessed by evaluating population distributions of i) percentage of the dosing interval with cefuroxime exposure above MIC, ii) time of cefuroxime exposure below MIC and iii) drug administered in excess to reach the efficacy target. Distributions were generated using wild type MIC distributions for two different species of bacteria, Escherichia coli and Streptococcus pneumoniae, obtained from the EUCAST database (2).
Results: Using a fixed MIC of 8 mg/L in the minimization, a large proportion of the population was exposed to sub-optimal exposure when evaluating using the E.coli MIC distribution. By increasing MIC to 16 mg/L, most of the individuals were treated sufficiently and an acceptable proportion was treated with drug in excess. When minimizing the risk function using MIC 0.25 mg/L and considering time of exposure below MIC it was possible to estimate dosing strategies that sufficiently treated S.pneumoniae with dose size 250 mg.
Conclusions: An approach for estimation of dosing strategies using data-based models and decision-based risk functions is illustrated. The results indicate that cefuroxime for treatment of E.coli bacteria may be inappropriate and that lower dose rates than currently used could be employed for S.pneumoniae.
References:
1. Viberg et al. Br J Clin Pharm (in press)
2. http://www.srga.org/eucastwt/WT_EUCAST.htm (2005-04-27)