Huang Zhiwei, Li Wenfang, Zhang Ruohao, Li Yi, Li Xin, Bian Xingchen, Zheng Shansong, Wang Xinmei, Zhang Ning, Gao Cong, Guo Beining, Wang Zhenling, Zhang Jing, Wu Xiaojie
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Front Microbiol. 2024 Dec 17;15:1516979. doi: 10.3389/fmicb.2024.1516979. eCollection 2024.
Pralurbactam (FL058) is a novel β-lactamase inhibitor with good inhibitory activity on class A, C, and D β-lactamases. This study aimed to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) relationship of pralurbactam/meropenem in a neutropenic murine thigh infection model.
After 2-h infection, neutropenic mice was treated with meropenem every 2 h alone or in combination with pralurbactam at different dosing frequencies for 24 h, and the colony count in the thighs was determined before and after treatment. The maximum effect model was fit to the PK/PD relationship to determine the PK/PD index and targets for pralurbactam in combination with meropenem resulting in a static effect and 1-log kill.
The plasma drug concentration-time data demonstrated that the PK profiles of pralurbactam were consistent with a one-compartment model. Pralurbactam demonstrated a linear PK profile in mice plasma. The percent time of free drug above 1 mg/L (%T > 1 mg/L) was the PK/PD index that best described the bacterial killing effect of pralurbactam/meropenem over 24 h. When the PK/PD index %T > 1 mg/L reached 38.4% and 63.6%, pralurbactam/meropenem combination would achieve bacteriostatic effect and 1-log reduction against in thigh bioburden, respectively.
These PK/PD data derived from mouse thigh infection models will be used to inform the optimal dosing regimen of pralurbactam/meropenem combination in clinical trials.
普拉巴坦（FL058）是一种新型β-内酰胺酶抑制剂，对A、C和D类β-内酰胺酶具有良好的抑制活性。本研究旨在评估普拉巴坦/美罗培南在中性粒细胞减少小鼠大腿感染模型中的药代动力学/药效学（PK/PD）关系。
感染2小时后，对中性粒细胞减少的小鼠每2小时单独给予美罗培南或与不同给药频率的普拉巴坦联合给药24小时，并在治疗前后测定大腿中的菌落计数。将最大效应模型拟合到PK/PD关系中，以确定普拉巴坦与美罗培南联合使用产生静态效应和1个对数级杀灭的PK/PD指数和靶点。
血浆药物浓度-时间数据表明，普拉巴坦的药代动力学特征与一室模型一致。普拉巴坦在小鼠血浆中呈现线性药代动力学特征。游离药物浓度高于1 mg/L的时间百分比（%T > 1 mg/L）是最能描述普拉巴坦/美罗培南在24小时内细菌杀灭效果的PK/PD指数。当PK/PD指数%T > 1 mg/L分别达到38.4%和63.6%时，普拉巴坦/美罗培南联合用药将分别对大腿生物负荷达到抑菌效果和1个对数级的降低。
这些来自小鼠大腿感染模型的PK/PD数据将用于指导普拉巴坦/美罗培南联合用药在临床试验中的最佳给药方案。
