Sanne van den Berg, Marie G L Attwood, Pippa Griffin, Sebastiaan D T Sassen, Anouk E Muller, Merel N Raaphorst, Maxime Gualtieri, Emilie Racine, Shampa Das, Alan R Noel, Joseph Meletiadis, Alasdair P MacGowan
{"title":"NOSO-502 的体外和体内药效学研究：确定主要药效学指标驱动因素。","authors":"Sanne van den Berg, Marie G L Attwood, Pippa Griffin, Sebastiaan D T Sassen, Anouk E Muller, Merel N Raaphorst, Maxime Gualtieri, Emilie Racine, Shampa Das, Alan R Noel, Joseph Meletiadis, Alasdair P MacGowan","doi":"10.1093/jac/dkae469","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>NOSO-5O2 is the first clinical candidate of a new antimicrobial class-the odilorhabdins. The pharmacodynamics of NOSO-502 were studied in vitro and in vivo to establish the pharmacodynamic index (PDI) driver.</p><p><strong>Methods: </strong>A dilutional pharmacokinetic system was used for in vitro experiments. In vivo experiments were conducted in the neutropenic murine thigh infection model. Three Escherichia coli and two Klebsiella pneumoniae strains were used. NOSO-502 pharmacokinetics (PK) in mice were described in a population PK model. Dose fractionation and escalation exposures were performed and bacteriostatic and 1 log10 and 2 log10 kill effects were determined using an Emax model. The coefficient of determination (R2) was used to estimate the variance that might be due to regression with various PDIs (fAUC/MIC, fCmax/MIC, %fT>MIC and fAUC/MIC per length of dosing interval fAUC/MIC·1/tau).</p><p><strong>Results: </strong>Exposure fractionation in both in vitro and in vivo studies indicated that 6-hourly dosing resulted in a greater reduction in K. pneumoniae bacterial burden compared with either 12- or 24-hourly dosing. Similar observations were made with three E. coli strains in vitro and a single strain of E. coli in vivo. For K. pneumoniae, R2 for fAUC/MIC·1/tau was 0.8376 in vitro and 0.6001 in vivo, which was greater than R2 with other PDIs. Analysis of pooled in vitro data from three strains of E. coli produced an R2 of 0.7073 for fAUC/MIC and 0.6100 for fAUC/MIC·1/tau.</p><p><strong>Conclusions: </strong>NOSO-502 exhibits both dose- and time-dependent in vitro and in vivo activity against both E. coli and K. pneumoniae.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9000,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pharmacodynamics of NOSO-502 studied in vitro and in vivo: determination of the dominant pharmacodynamic index driver.\",\"authors\":\"Sanne van den Berg, Marie G L Attwood, Pippa Griffin, Sebastiaan D T Sassen, Anouk E Muller, Merel N Raaphorst, Maxime Gualtieri, Emilie Racine, Shampa Das, Alan R Noel, Joseph Meletiadis, Alasdair P MacGowan\",\"doi\":\"10.1093/jac/dkae469\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>NOSO-5O2 is the first clinical candidate of a new antimicrobial class-the odilorhabdins. The pharmacodynamics of NOSO-502 were studied in vitro and in vivo to establish the pharmacodynamic index (PDI) driver.</p><p><strong>Methods: </strong>A dilutional pharmacokinetic system was used for in vitro experiments. In vivo experiments were conducted in the neutropenic murine thigh infection model. Three Escherichia coli and two Klebsiella pneumoniae strains were used. NOSO-502 pharmacokinetics (PK) in mice were described in a population PK model. Dose fractionation and escalation exposures were performed and bacteriostatic and 1 log10 and 2 log10 kill effects were determined using an Emax model. The coefficient of determination (R2) was used to estimate the variance that might be due to regression with various PDIs (fAUC/MIC, fCmax/MIC, %fT>MIC and fAUC/MIC per length of dosing interval fAUC/MIC·1/tau).</p><p><strong>Results: </strong>Exposure fractionation in both in vitro and in vivo studies indicated that 6-hourly dosing resulted in a greater reduction in K. pneumoniae bacterial burden compared with either 12- or 24-hourly dosing. Similar observations were made with three E. coli strains in vitro and a single strain of E. coli in vivo. For K. pneumoniae, R2 for fAUC/MIC·1/tau was 0.8376 in vitro and 0.6001 in vivo, which was greater than R2 with other PDIs. Analysis of pooled in vitro data from three strains of E. coli produced an R2 of 0.7073 for fAUC/MIC and 0.6100 for fAUC/MIC·1/tau.</p><p><strong>Conclusions: </strong>NOSO-502 exhibits both dose- and time-dependent in vitro and in vivo activity against both E. coli and K. pneumoniae.</p>\",\"PeriodicalId\":14969,\"journal\":{\"name\":\"Journal of Antimicrobial Chemotherapy\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2025-01-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Antimicrobial Chemotherapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/jac/dkae469\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"INFECTIOUS DISEASES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Antimicrobial Chemotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/jac/dkae469","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"INFECTIOUS DISEASES","Score":null,"Total":0}
Pharmacodynamics of NOSO-502 studied in vitro and in vivo: determination of the dominant pharmacodynamic index driver.
Background: NOSO-5O2 is the first clinical candidate of a new antimicrobial class-the odilorhabdins. The pharmacodynamics of NOSO-502 were studied in vitro and in vivo to establish the pharmacodynamic index (PDI) driver.
Methods: A dilutional pharmacokinetic system was used for in vitro experiments. In vivo experiments were conducted in the neutropenic murine thigh infection model. Three Escherichia coli and two Klebsiella pneumoniae strains were used. NOSO-502 pharmacokinetics (PK) in mice were described in a population PK model. Dose fractionation and escalation exposures were performed and bacteriostatic and 1 log10 and 2 log10 kill effects were determined using an Emax model. The coefficient of determination (R2) was used to estimate the variance that might be due to regression with various PDIs (fAUC/MIC, fCmax/MIC, %fT>MIC and fAUC/MIC per length of dosing interval fAUC/MIC·1/tau).
Results: Exposure fractionation in both in vitro and in vivo studies indicated that 6-hourly dosing resulted in a greater reduction in K. pneumoniae bacterial burden compared with either 12- or 24-hourly dosing. Similar observations were made with three E. coli strains in vitro and a single strain of E. coli in vivo. For K. pneumoniae, R2 for fAUC/MIC·1/tau was 0.8376 in vitro and 0.6001 in vivo, which was greater than R2 with other PDIs. Analysis of pooled in vitro data from three strains of E. coli produced an R2 of 0.7073 for fAUC/MIC and 0.6100 for fAUC/MIC·1/tau.
Conclusions: NOSO-502 exhibits both dose- and time-dependent in vitro and in vivo activity against both E. coli and K. pneumoniae.
期刊介绍：
The Journal publishes articles that further knowledge and advance the science and application of antimicrobial chemotherapy with antibiotics and antifungal, antiviral and antiprotozoal agents. The Journal publishes primarily in human medicine, and articles in veterinary medicine likely to have an impact on global health.
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