Pharmacokinetics and Pharmacodynamics of Nemonoxacin in a Neutropenic Murine Lung Infection Model Against Streptococcus Pneumoniae
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 Streptococcus pneumoniae using a neutropenic murine lung infection model. Single-dose PK analy...
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Frontiers Media S.A.
2021-05-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.658558/full |
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| author | Xin Li Xin Li Xin Li Yuancheng Chen Xiaoyong Xu Xiaoyong Xu Yi Li Yi Li Yi Li Yaxin Fan Yaxin Fan Yaxin Fan Xiaofen Liu Xiaofen Liu Xiaofen Liu Xingchen Bian Xingchen Bian Xingchen Bian Xingchen Bian Hailan Wu Hailan Wu Hailan Wu Xu Zhao Meiqing Feng Beining Guo Beining Guo Beining Guo Jing Zhang Jing Zhang Jing Zhang Jing Zhang |
| author_facet | Xin Li Xin Li Xin Li Yuancheng Chen Xiaoyong Xu Xiaoyong Xu Yi Li Yi Li Yi Li Yaxin Fan Yaxin Fan Yaxin Fan Xiaofen Liu Xiaofen Liu Xiaofen Liu Xingchen Bian Xingchen Bian Xingchen Bian Xingchen Bian Hailan Wu Hailan Wu Hailan Wu Xu Zhao Meiqing Feng Beining Guo Beining Guo Beining Guo Jing Zhang Jing Zhang Jing Zhang Jing Zhang |
| author_sort | Xin Li |
| collection | DOAJ |
| description | 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 Streptococcus pneumoniae 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 (Cmax) 0.56–7.32 mg/L, area under the concentration-time curve from 0 to 24 h (AUC0-24) 0.67–26.10 mg·h/L, and elimination half-life (T1/2) 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 Emax Hill equation was used to describe the dose-response data. The free-drug plasma fAUC0-24/MIC ratio was considered the PK/PD index most closely associated with efficacy (R2 0.9268). Median fAUC0-24/MIC associated with static, 1-log10 and 2-log10 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 S. pneumoniae. |
| first_indexed | 2024-12-16T12:11:12Z |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-16T12:11:12Z |
| publishDate | 2021-05-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-79010917335c4a52ad9ceb2d26afc9a02022-12-21T22:32:12ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-05-011210.3389/fphar.2021.658558658558Pharmacokinetics and Pharmacodynamics of Nemonoxacin in a Neutropenic Murine Lung Infection Model Against Streptococcus PneumoniaeXin Li0Xin Li1Xin Li2Yuancheng Chen3Xiaoyong Xu4Xiaoyong Xu5Yi Li6Yi Li7Yi Li8Yaxin Fan9Yaxin Fan10Yaxin Fan11Xiaofen Liu12Xiaofen Liu13Xiaofen Liu14Xingchen Bian15Xingchen Bian16Xingchen Bian17Xingchen Bian18Hailan Wu19Hailan Wu20Hailan Wu21Xu Zhao22Meiqing Feng23Beining Guo24Beining Guo25Beining Guo26Jing Zhang27Jing Zhang28Jing Zhang29Jing Zhang30Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaKey Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, ChinaNational Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, ChinaPhase I Unit, Huashan Hospital, Fudan University, Shanghai, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaKey Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaKey Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, ChinaNational Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaKey Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, ChinaNational Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaKey Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, ChinaNational Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaKey Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, ChinaNational Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, ChinaDepartment of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaKey Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, ChinaNational Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaDepartment of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaKey Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, ChinaNational Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, ChinaKey Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, ChinaNational Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, ChinaPhase I Unit, Huashan Hospital, Fudan University, Shanghai, ChinaNemonoxacin, 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 Streptococcus pneumoniae 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 (Cmax) 0.56–7.32 mg/L, area under the concentration-time curve from 0 to 24 h (AUC0-24) 0.67–26.10 mg·h/L, and elimination half-life (T1/2) 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 Emax Hill equation was used to describe the dose-response data. The free-drug plasma fAUC0-24/MIC ratio was considered the PK/PD index most closely associated with efficacy (R2 0.9268). Median fAUC0-24/MIC associated with static, 1-log10 and 2-log10 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 S. pneumoniae.https://www.frontiersin.org/articles/10.3389/fphar.2021.658558/fullnemonoxacinpharmacokinetics/pharmacodynamicsstreptococcus pneumoniaeneutropenic murine lung infection modelbreakpoint |
| spellingShingle | Xin Li Xin Li Xin Li Yuancheng Chen Xiaoyong Xu Xiaoyong Xu Yi Li Yi Li Yi Li Yaxin Fan Yaxin Fan Yaxin Fan Xiaofen Liu Xiaofen Liu Xiaofen Liu Xingchen Bian Xingchen Bian Xingchen Bian Xingchen Bian Hailan Wu Hailan Wu Hailan Wu Xu Zhao Meiqing Feng Beining Guo Beining Guo Beining Guo Jing Zhang Jing Zhang Jing Zhang Jing Zhang Pharmacokinetics and Pharmacodynamics of Nemonoxacin in a Neutropenic Murine Lung Infection Model Against Streptococcus Pneumoniae Frontiers in Pharmacology nemonoxacin pharmacokinetics/pharmacodynamics streptococcus pneumoniae neutropenic murine lung infection model breakpoint |
| title | Pharmacokinetics and Pharmacodynamics of Nemonoxacin in a Neutropenic Murine Lung Infection Model Against Streptococcus Pneumoniae |
| title_full | Pharmacokinetics and Pharmacodynamics of Nemonoxacin in a Neutropenic Murine Lung Infection Model Against Streptococcus Pneumoniae |
| title_fullStr | Pharmacokinetics and Pharmacodynamics of Nemonoxacin in a Neutropenic Murine Lung Infection Model Against Streptococcus Pneumoniae |
| title_full_unstemmed | Pharmacokinetics and Pharmacodynamics of Nemonoxacin in a Neutropenic Murine Lung Infection Model Against Streptococcus Pneumoniae |
| title_short | Pharmacokinetics and Pharmacodynamics of Nemonoxacin in a Neutropenic Murine Lung Infection Model Against Streptococcus Pneumoniae |
| title_sort | pharmacokinetics and pharmacodynamics of nemonoxacin in a neutropenic murine lung infection model against streptococcus pneumoniae |
| topic | nemonoxacin pharmacokinetics/pharmacodynamics streptococcus pneumoniae neutropenic murine lung infection model breakpoint |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.658558/full |
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