Lim H-S, Chong Y P, Noh Y-H, Jung J-A, Kim Y S
Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
J Clin Pharm Ther. 2014 Apr;39(2):196-203. doi: 10.1111/jcpt.12123. Epub 2014 Jan 16.
Vancomycin is the drug of choice for methicillin-resistant Staphylococcus aureus (MRSA) infection and shows time-dependent bacterial killing. The current study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of vancomycin and explored its optimal dosing regimens by modeling and simulation.
Pharmacokinetics study was performed for 20 patients who were treated with vancomycin intravenously, 1000 mg, every 12 h, and blood for PK was randomly drawn within prespecified time windows. PD study was in vitro time-kill experiment for vancomycin against 20 MRSA strains independent of the PK study, where bacterial titre was measured at 0, 2, 4, 8, 24 h after the beginning of vancomycin exposure at 0, 1, 2, 4, 8, 16, 32× minimum inhibitory concentrations. PK and PD models were built from each data set, and simulation for MRSA titre changes over time in human body was performed for various vancomycin dosing regimens using NONMEM(®) .
Vancomycin followed a two-compartment PK model, and creatinine clearance was the significant covariate affecting the clearance of vancomycin. PD model described the in vitro time-kill data well. The PK/PD model predicted clear dose-response relationships of vancomycin. The therapeutic dosing regimens of vancomycin, suggested by the simulation studies, showed good agreement with the current clinical practice guidance, which indicates that this PK/PD modeling and simulation approach could prove useful for identifying optimal dosing regimens of other antibiotics and expediting novel antibiotic development. Using PD model from in vitro time-kill study and human PK model from phase 1 study, we could predict whether the drug is going to be efficacious or obtain insight into the optimal dosing regimens for a novel antibiotic agent in the early phases of drug development process.
万古霉素是耐甲氧西林金黄色葡萄球菌（MRSA）感染的首选药物，具有时间依赖性杀菌作用。本研究评估了万古霉素的药代动力学（PK）和药效动力学（PD），并通过建模和模拟探索其最佳给药方案。
对20例接受万古霉素静脉滴注治疗（每12小时1000mg）的患者进行药代动力学研究，在预定时间窗内随机采集血样用于PK分析。药效动力学研究是针对万古霉素对20株MRSA菌株进行的体外时间杀菌实验，独立于药代动力学研究，在万古霉素暴露开始后0、1、2、4、8、16、32倍最小抑菌浓度时，于0、2、4、8、24小时测量细菌滴度。根据每个数据集建立PK和PD模型，并使用NONMEM(®)对各种万古霉素给药方案进行人体MRSA滴度随时间变化的模拟。
万古霉素遵循二室药代动力学模型，肌酐清除率是影响万古霉素清除的显著协变量。药效动力学模型能很好地描述体外时间杀菌数据。PK/PD模型预测了万古霉素明确的剂量反应关系。模拟研究提出的万古霉素治疗给药方案与当前临床实践指南高度一致，这表明这种PK/PD建模和模拟方法可能有助于确定其他抗生素的最佳给药方案，并加速新型抗生素的研发。利用体外时间杀菌研究的药效动力学模型和1期研究的人体药代动力学模型，我们可以预测药物是否有效，或在药物研发过程的早期阶段深入了解新型抗生素的最佳给药方案。
