体外和体内研究的NOSO-502药效学：主要药效学指标驱动因素的确定

Pharmacodynamics of NOSO-502 studied in vitro and in vivo: determination of the dominant pharmacodynamic index driver.

作者信息

van den Berg Sanne, Attwood Marie G L, Griffin Pippa, Sassen Sebastiaan D T, Muller Anouk E, Raaphorst Merel N, Gualtieri Maxime, Racine Emilie, Das Shampa, Noel Alan R, Meletiadis Joseph, MacGowan Alasdair P

机构信息

Department of Medical Microbiology and Infectious Diseases, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.

CATOR, Center for Antimicrobial Treatment Optimization Rotterdam, Rotterdam, The Netherlands.

出版信息

J Antimicrob Chemother. 2025 Mar 3;80(3):752-759. doi: 10.1093/jac/dkae469.

DOI:10.1093/jac/dkae469

PMID:39804217

Abstract

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.

摘要

背景

NOSO-5O2是新型抗菌药物类——杀线虫杆菌素的首个临床候选药物。对NOSO-502的药效学进行了体外和体内研究，以确定药效学指标（PDI）驱动因素。

方法

采用稀释药代动力学系统进行体外实验。在中性粒细胞减少的小鼠大腿感染模型中进行体内实验。使用了三株大肠杆菌和两株肺炎克雷伯菌。在群体药代动力学模型中描述了小鼠体内的NOSO-502药代动力学（PK）。进行了剂量分割和递增暴露，并使用Emax模型确定抑菌以及1 log10和2 log10杀灭效果。决定系数（R2）用于估计可能因各种PDI（fAUC/MIC、fCmax/MIC、%fT>MIC以及给药间隔长度的fAUC/MIC·1/tau）回归导致的方差。

结果

体外和体内研究中的暴露分割表明，与每12小时或24小时给药相比，每6小时给药导致肺炎克雷伯菌细菌载量的降低幅度更大。在体外对三株大肠杆菌以及在体内对一株大肠杆菌也有类似观察结果。对于肺炎克雷伯菌，fAUC/MIC·1/tau的R2在体外为0.8376，在体内为0.6001，大于其他PDI的R2。对来自三株大肠杆菌的汇总体外数据进行分析，fAUC/MIC的R2为0.7073，fAUC/MIC·1/tau的R2为0.6100。