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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Pharmacology of Infectious Diseases
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1476158

Model-guided Development of Pharmacokinetic/Pharmacody-2 namic Cut-offs and Evaluation of Sitafloxacin Dosing Regi-3 mens against Target Pathogens 4

Provisionally accepted
Hailan Wu Hailan Wu Yi Li Yi Li Xin Li Xin Li Yaxin Fan Yaxin Fan Beining Guo Beining Guo Xiaofen Liu Xiaofen Liu Wanzhen Li Wanzhen Li Mengting Chen Mengting Chen Yan Chen Yan Chen Jing Zhang Jing Zhang *
  • Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China

The final, formatted version of the article will be published soon.

    To identify the pharmacokinetic/pharmacodynamic (PK/PD) cut-offs for using sitafloxacin against 16 target pathogens to support clinical breakpoint establishment for antimicrobial drug sensitivity testing, a pop-17 ulation PK (PopPK) model was built (342 subjects) to calculate the dosing-regimen-dependent (50 mg q12h, 18 100 mg q24h and 100 mg q12h) PK parameters of sitafloxacin-infected patients, which were combined with 19 in vitro PD data and PK/PD target data. The probabilities of attainment (PTAs) and cumulative fraction of 20 response (CFR) values for different sitafloxacin dosing regimens against Streptococcus pneumoniae, Staphy-21 lococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa were calculated via 22 Monte Carlo simulation. PopPK modelling revealed that the PK profile of sitafloxacin was consistent with a 23 two-compartment model with first-order elimination. Creatinine clearance affected total clearance, body 24 weight and age affected the central ventricular apparent volume of distribution, and food affected the sitaflox-25 acin absorption rate. On the basis of the animal infection model target (fAUC24h/MIC=11.56), the anti-Strep-26 tococcus pneumoniae sitafloxacin dosing regimen PTAs were >95% (MIC≤0.06, ≤0.06, ≤0.125 mg/L; 27 CFRs=98.2~99.3%). With a clinical study target of fAUC24h/MIC≥30, the anti-Streptococcus pneumoniae 28 dosing regimen PTAs were >95% (MIC≤0.03, ≤0.03, ≤0.06 mg/L; CFRs=89.2~97.3%). For the other four 29 strains, the dosing-regimen-dependent sitafloxacin PK/PD cut-offs were 0.06, 0.06 and 0.125 mg/L, respec-30 tively (CFRs=56.3~76.9%). Our findings suggest that sitafloxacin PK/PD cut-offs of S≤0.06 mg/L and 31 R>0.125 mg/L should be used against these five strains and that the sitafloxacin dosing regimens (50 mg q12h, 32 100 mg q24h and 100 mg q12h) have the expected efficacy against Streptococcus pneumoniae-related infec-33 tions, but the efficacy against Pseudomonas aeruginosa-associated infections needs to be verified in clinical 34 practice.

    Keywords: Sitafloxacin, PK/PD cut-offs, population pharmacokinetics, Monte Carlo simulation, infected pa-36 tients, probability of target attainment, cumulative percent response 37 38

    Received: 05 Aug 2024; Accepted: 14 Jan 2025.

    Copyright: © 2025 Wu, Li, Li, Fan, Guo, Liu, Li, Chen, Chen and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jing Zhang, Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.