Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, China.
Center for Drug Evaluation, China Food and Drug Administration, Beijing 100038, China.
Acta Pharmacol Sin. 2018 Feb;39(2):286-293. doi: 10.1038/aps.2017.57. Epub 2017 Aug 24.
Vancomycin, a glycopeptide antibiotic for the treatment of grampositive infections, is mainly eliminated via glomerular filtration. Thus, its therapeutic effects are affected predominantly by renal function. The aim of this study was to develop a population pharmacokinetic model of vancomycin for Chinese adult patients and to investigate the influence of different renal function descriptors on the predictability of the model. A retrospective analysis was performed based on the blood concentrations of vancomycin in 218 Chinese adult patients. Among these patients, the data from 160 were used to establish the population pharmacokinetic model, and the data from the remaining 58 patients were used for external model validation. A simulation was employed to determine the appropriate initial vancomycin dosage regimens in adult Chinese patients for reaching the target steady-state trough concentrations of 10-15 mg/L and 15-20 mg/L. We developed a one-compartment model with first-order absorption to characterize the concentration-time profile of vancomycin. There was a positive correlation between the body clearance of vancomycin and renal function; both creatinine clearance (CL) and age were the covariates that influenced the PK of vancomycin, and the excretion of vancomycin decreased as renal function diminishing with age. The typical clearance (CL) value was 2.829 L/h for 75-year-old patients with CL values of 80 mL/min, and the rate constant of CL with the CL changing at 1 mL/min was 0.00842. The influence coefficient of age on CL was 0.08143. The external validation results revealed that the current different descriptors of renal function behaved similarly to the predicted performance of the models. In conclusion, the developed model is appropriate for Bayesian dose predictions of vancomycin concentrations in the population of Chinese adult patients. Furthermore, the simulation provides a reference for clinical optimized antibacterial therapy with vancomycin.
万古霉素是一种治疗革兰氏阳性感染的糖肽类抗生素，主要通过肾小球滤过消除。因此，其治疗效果主要受肾功能影响。本研究旨在建立中国成年患者万古霉素的群体药代动力学模型，并探讨不同肾功能指标对模型预测能力的影响。基于 218 例中国成年患者的万古霉素血药浓度进行回顾性分析。其中，160 例患者的数据用于建立群体药代动力学模型，其余 58 例患者的数据用于外部模型验证。通过模拟确定中国成年患者达到目标稳态谷浓度 10-15mg/L 和 15-20mg/L 的合适初始万古霉素剂量方案。我们开发了一个具有一级吸收的单室模型来描述万古霉素的浓度-时间曲线。万古霉素的清除率与肾功能呈正相关；肌酐清除率（CL）和年龄是影响万古霉素药代动力学的协变量，随着肾功能的降低，万古霉素的排泄减少。对于 CL 值为 80ml/min 的 75 岁患者，典型清除率（CL）值为 2.829L/h，CL 每变化 1ml/min 时的 CL 速率常数为 0.00842。年龄对 CL 的影响系数为 0.08143。外部验证结果表明，目前不同的肾功能描述符与模型的预测性能表现相似。结论：所建立的模型适用于中国成年患者万古霉素群体药代动力学浓度的贝叶斯剂量预测。此外，模拟为万古霉素临床优化抗菌治疗提供了参考。
