Li Xin, Chen Yuancheng, Xu Xiaoyong, Li Yi, Fan Yaxin, Liu Xiaofen, Bian Xingchen, Wu Hailan, Zhao Xu, Feng Meiqing, Guo Beining, Zhang Jing
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, China.
Front Pharmacol. 2021 May 4;12:658558. doi: 10.3389/fphar.2021.658558. eCollection 2021.
Nemonoxacin, a novel nonfluorinated quinolone for the treatment of community-acquired pneumonia. We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets and PK/PD breakpoints of nemonoxacin against using a neutropenic murine lung infection model. Single-dose PK analysis after subcutaneous administration of nemonoxacin at doses from 2.5 to 80 mg/kg showed maximum plasma concentration (C) 0.56-7.32 mg/L, area under the concentration-time curve from 0 to 24 h (AUC) 0.67-26.10 mg·h/L, and elimination half-life (T) 0.8-1.4 h. The epithelial lining fluid (ELF) penetration ratio of total drug was 1.40. Dose fractionation (1.25-80 mg/kg/day, every 24, 12, 8, and 6 h) and dose escalation studies (1.25-160 mg/kg, every 24 h) were conducted. The sigmoid E Hill equation was used to describe the dose-response data. The free-drug plasma AUC/MIC ratio was considered the PK/PD index most closely associated with efficacy (R 0.9268). Median AUC/MIC associated with static, 1-log and 2-log CFU reduction from baseline were 8.6, 23.2 and 44.4, respectively. Monte Carlo simulation showed 500 mg qd and 750 mg qd oral doses of nemonoxacin were able to achieve 90% probability of target attainment (PTA) against bacteria with MIC of 0.5 mg/L and 1 mg/L. We recommended susceptibility (S) ≤ 0.5 mg/L, intermediate (I) = 1 mg/L and resistant (R) ≥ 2 mg/L as the PK/PD breakpoints for nemonoxacin against .
奈诺沙星是一种用于治疗社区获得性肺炎的新型非氟喹诺酮类药物。我们使用中性粒细胞减少小鼠肺部感染模型报告了奈诺沙星对[具体细菌]的药代动力学/药效学（PK/PD）靶点和PK/PD折点。皮下注射2.5至80 mg/kg剂量的奈诺沙星后的单剂量PK分析显示，最大血浆浓度（Cmax）为0.56 - 7.32 mg/L，0至24小时浓度-时间曲线下面积（AUC0 - 24h）为0.67 - 26.10 mg·h/L，消除半衰期（t1/2）为0.8 - 1.4小时。总药物的上皮衬液（ELF）渗透比为1.40。进行了剂量分割（1.25 - 80 mg/kg/天，每24、12、8和6小时一次）和剂量递增研究（1.25 - 160 mg/kg，每24小时一次）。采用S型E Hill方程描述剂量反应数据。游离药物血浆AUC/MIC比值被认为是与疗效最密切相关的PK/PD指数（R2 = 0.9268）。与从基线静态、1-log和2-log CFU减少相关的中位AUC/MIC分别为8.6、23.2和44.4。蒙特卡洛模拟显示，口服500 mg qd和750 mg qd剂量的奈诺沙星能够对MIC为0.5 mg/L和1 mg/L的细菌达到90%的目标达成概率（PTA）。我们建议将敏感性（S）≤ 0.5 mg/L、中介（I）= 1 mg/L和耐药（R）≥ 2 mg/L作为奈诺沙星对[具体细菌]的PK/PD折点。
