新型噁唑烷酮类抗生素体内药代动力学-药效学研究

New Oxazolidinone MRX-I PK-PD study

目的:建立小鼠PK/PD模型,评价新型噁唑烷酮类抗菌药MRX-I体内的药代动力学、药效学(PK/PD)特征,考察体内药物浓度与治疗效果随时间变化的关系,将在研抗菌药物MRX-I的临床前动物试验结果与其临床适应症衔接起来。方法:通过免疫低下小鼠腿部感染模型开展MRX-I的体内PK/PD的研究,根据PK/PD结果用非线性回归方法分析得到最佳PK/PD参数,同时用S型最大效应模型评估该药对受试菌的静息剂量。结果:在免疫低下小鼠的腿部感染模型中,MRX-I对受试金黄色葡萄球菌的MIC值为1~2μg/m L,单剂量口服给予20mg/kg和80mg/kg,Cmax分别为16.2μg/m L和46.0μg/m L,AUC24h分别为30.8μg*h/m L和121.0μg*h/m L,多剂量多次给药试验表明PK/PD参数的相关性分别为%T>MIC R2=62.9%,AUC24h/MIC R2=91.1%和Cmax/MIC R2=86.0%。8株金黄色葡萄球菌受试菌(含4株MSSA、4株MRSA)的静息剂量为22.0~140.0mg/kg/24h[均值(77.0±39.7)mg/kg/24h]。结论:AUC24h/MIC为MRX-I的最佳PK/PD参数,与Linezolid表现一致。MRX-I对革兰氏阳性菌导致的局部感染具有良好的抗菌活性。

Objective：Set up PK/PD model, evaluated the efficacy and characterized the in vivo pharmacokinetic/pharmacodynamic（PD） characteristics. Methods：Establish neutropenic miee thigh infection model with S. aureus, to characterize the in vivo PK/PD, nonlinear regression analysis was employed to determine which PK/PD parameter best correlated with bactericidal efficacy, and eaculate the static dose with S model. Results：Following a single oral dose of 20 and 80mg/kg in mice with S. aureus infection （MIC = 1-2μg/mL against S. aureus）, Cmax was 16.2 and 46.0μg/mL and AUC24h, 30.8 and 121.0μg＊h /mL, respectively. In dose fractionation studies, against S. aureus with R2=91.1% for AUC24h/MIC, versus R2 = 62.9% for %T〉MIC and R2 = 86.0% for the Cmax/MIC. The static doses against eight strains of S. aureus （four MRSA and four MSSA） ranged from 22.0 to 140.0mg/kg/24h with a mean of 77.0±39.7mg/kg/24h. Conclusion： The AUCiJMIC was determined to be the best correlated PKPD parameter predicting MRX-I efficacy, which was similar to Linezolid. MRX-I showed good in vivo efficacy against S. aureus strains.