期刊
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
卷 72, 期 4, 页码 1129-1136出版社
OXFORD UNIV PRESS
DOI: 10.1093/jac/dkw553
关键词
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资金
- National Institute of Biomedical Imaging and Bioengineering of the NIH [P41-EB001978]
- Alfred E. Mann Institute at the University of Southern California
Objectives: The macrolide antibiotic roxithromycin has seen widespread clinical use for several decades; however, no population pharmacokinetic analysis has been published. Early studies indicated saturation of protein binding and absorption at doses within the approved range, which may impact pharmacodynamic target attainment since regimens of 150 mg twice daily and 300 mg once daily are used interchangeably in clinical practice. This study aimed to develop a population-based meta-analysis of roxithromycin pharmacokinetics, and utilize this model to inform optimal dosing regimens. Methods: Following an extensive search, roxithromycin pharmacokinetic data were collected or digitized from literature publications. Population pharmacokinetic modelling was undertaken with ADAPT. Dosing simulations were performed to investigate differences in exposure and pharmacodynamic target attainment between dosing regimens. Results: A two-compartment model with saturable absorption described the data (n = 63); changes in free drug exposure were simulated using a saturable protein binding model. Simulations indicated that a 300 mg daily regimen achieves a 37% and 53% lower total or free AUC (fAUC), respectively, compared with 150 mg twice daily. These pharmacokinetic differences translated to significantly lower target attainment (fAUC/MIC ratio >20) with a 300 mg daily regimen at MICs of 0.5 and 1 mg/L (51% and 7%) compared with patients receiving 150 mg twice daily (82% and 54%). Conclusions: Roxithromycin displays saturable absorption and protein binding leading to lower exposure and lower target attainment at MICs >0.5 mg/L with widely used once-daily dosing regimens, indicating that twice-daily regimens may be preferable for pathogens less susceptible to roxithromycin.
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