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Nemonoxacin Dosage Adjustment in Patients with Severe Renal Impairment Based on Population Pharmacokinetic and Pharmacodynamic Analysis
  • +17
  • Yi Li,
  • Jianda Lu,
  • Yue Kang,
  • Xiaoyong Xu,
  • Xin Li,
  • Yuancheng Chen,
  • Kun Wang,
  • Xiaofen Liu,
  • Yaxin Fan,
  • Hailan Wu,
  • Yu Wang,
  • Jiali Hu,
  • Jicheng Yu,
  • Jufang Wu,
  • Beining Guo,
  • Yingyuan Zhang,
  • Xin Zeng,
  • Ming Zhao,
  • Jun Xue,
  • Jing Zhang
Yi Li
Fudan University Huashan Hospital Institute of Antibiotics
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Jianda Lu
Fudan University Huashan Hospital Department of Nephrology
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Yue Kang
Fudan University Huashan Hospital Institute of Antibiotics
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Xiaoyong Xu
Fudan University Huashan Hospital Institute of Antibiotics
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Xin Li
Fudan University Huashan Hospital Institute of Antibiotics
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Yuancheng Chen
Huashan Hospital Fudan University
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Kun Wang
Shanghai Medical University
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Xiaofen Liu
Fudan University Huashan Hospital Institute of Antibiotics
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Yaxin Fan
Fudan University Huashan Hospital Institute of Antibiotics
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Hailan Wu
Fudan University Huashan Hospital Institute of Antibiotics
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Yu Wang
Fudan University Huashan Hospital Institute of Antibiotics
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Jiali Hu
Fudan University Huashan Hospital Institute of Antibiotics
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Jicheng Yu
Huashan Hospital Fudan University
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Jufang Wu
Huashan Hospital Fudan University
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Beining Guo
Fudan University Huashan Hospital Institute of Antibiotics
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Yingyuan Zhang
Fudan University Huashan Hospital Institute of Antibiotics
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Xin Zeng
Fudan University Huashan Hospital Institute of Antibiotics
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Ming Zhao
National Medical Products Administration
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Jun Xue
Fudan University Huashan Hospital Department of Nephrology
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Jing Zhang
Fudan University Huashan Hospital Institute of Antibiotics
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Abstract

Aims: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic/pharmacodynamic (PPK/PD) analysis. Methods: The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of 0.5 g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 48 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) against S. Pneumoniae and S. aureus was calculated by Monte Carlo simulation. Results: The data best fitted to a two-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L), and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4±6.5% in severe renal impairment patients and 66.1±16.8% in healthy controls. PPK/PD modeling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g q48h was the optimal dosing regimen in severe renal impairment patients, evidenced by higher PTA (92.7%) and CFR (>99%) at nemonoxacin MIC ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if MIC ≤ 0.5 mg/L. Conclusion: An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.

Peer review status:ACCEPTED

21 Jan 2021Submitted to British Journal of Clinical Pharmacology
23 Jan 2021Submission Checks Completed
23 Jan 2021Assigned to Editor
26 Jan 2021Reviewer(s) Assigned
01 Mar 2021Review(s) Completed, Editorial Evaluation Pending
04 Mar 2021Editorial Decision: Revise Major
02 Apr 20211st Revision Received
03 Apr 2021Submission Checks Completed
03 Apr 2021Assigned to Editor
03 Apr 2021Review(s) Completed, Editorial Evaluation Pending
15 Apr 2021Editorial Decision: Accept