Ahmed Hifza, Böhmdorfer Michaela, Jäger Walter, Zeitlinger Markus
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Department of Clinical Pharmacy, University of Vienna, Vienna, Austria.
J Antimicrob Chemother. 2025 Feb 3;80(2):363-371. doi: 10.1093/jac/dkae412.
In the preclinical development of new drugs, animal models are often employed to predict their efficacy in humans, relying on translational pharmacokinetic/pharmacodynamic (PK/PD) studies. We performed in vitro experiments focusing on the comparison of plasma protein binding (PPB) and bacterial growth dynamics of clindamycin, a commonly used antimicrobial agent, across a range of drug concentrations and plasma environments.
Human, bovine and rat plasma were used for determining PPB of clindamycin at various antibiotic concentrations in buffer and media containing 20% to 70% plasma or pure plasma using ultrafiltration (UF) and equilibrium dialysis (ED). Also bacterial growth and time-kill assays were performed in Mueller-Hinton broth (MHB) containing various percentages of plasma.
Protein binding of clindamycin correlated well between UF and ED. Notably, clindamycin exhibited substantially lower protein binding to rat plasma compared with human and bovine plasma. Staphylococcus aureus growth was significantly reduced in 70% human, bovine, and rat plasma after 4, 8 and 24 h compared with standard MHB. Time-kill data demonstrated that bacterial counts at both 20% and 70% plasmas were less when compared with MHB at drug concentrations lower than MIC after 4 and 8 h of incubation. For rat plasma, the difference was maintained over 24 h of incubation. Furthermore, a complete bacterial killing at 16 mg/L was observed after 24 h in 20% and 70% human and bovine plasma, but not for rat plasma.
Recognizing interspecies differences in PB might be essential for optimizing the translational relevance of preclinical studies.
在新药的临床前开发中，动物模型常被用于通过转化药代动力学/药效学（PK/PD）研究来预测其对人类的疗效。我们进行了体外实验，重点比较了常用抗菌药物克林霉素在一系列药物浓度和血浆环境下的血浆蛋白结合率（PPB）和细菌生长动力学。
使用人、牛和大鼠血浆，通过超滤（UF）和平衡透析（ED）法测定克林霉素在含有20%至70%血浆或纯血浆的缓冲液和培养基中不同抗生素浓度下的PPB。此外，还在含有不同百分比血浆的 Mueller-Hinton 肉汤（MHB）中进行了细菌生长和时间杀菌试验。
UF和ED法测得的克林霉素蛋白结合率相关性良好。值得注意的是，与人和牛血浆相比，克林霉素与大鼠血浆的蛋白结合率显著降低。与标准MHB相比，金黄色葡萄球菌在70%的人、牛和大鼠血浆中培养4、8和24小时后生长明显受到抑制。时间杀菌数据表明，在药物浓度低于最低抑菌浓度（MIC）时，培养4和8小时后，20%和70%血浆中的细菌数量均低于MHB中的细菌数量。对于大鼠血浆，在24小时的培养过程中这种差异一直存在。此外，在20%和70%的人及牛血浆中，24小时后在16mg/L时观察到完全杀菌，但大鼠血浆中未观察到。
认识到种间血浆蛋白结合率的差异对于优化临床前研究的转化相关性可能至关重要。
