Yoon Sukyong, Guk Jinju, Lee Sang-Guk, Chae Dongwoo, Kim Jeong-Ho, Park Kyungsoo
Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea.
Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
Front Pharmacol. 2023 Oct 9;14:1252757. doi: 10.3389/fphar.2023.1252757. eCollection 2023.
While vancomycin remains a widely prescribed antibiotic, it can cause ototoxicity and nephrotoxicity, both of which are concentration-associated. Overtreatment can occur when the treatment lasts for an unnecessarily long time. Using a model-informed precision dosing scheme, this study aims to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for vancomycin to determine the optimal dosage regimen and treatment duration in order to avoid drug-induced toxicity. The data were obtained from electronic medical records of 542 patients, including 40 children, and were analyzed using NONMEM software. For PK, vancomycin concentrations were described with a two-compartment model incorporating allometry scaling. This revealed that systemic clearance decreased with creatinine and blood urea nitrogen levels, history of diabetes and renal diseases, and further decreased in women. On the other hand, the central volume of distribution increased with age. For PD, C-reactive protein (CRP) plasma concentrations were described by transit compartments and were found to decrease with the presence of pneumonia. Simulations demonstrated that, given the model informed optimal doses, peak and trough concentrations as well as the area under the concentration-time curve remained within the therapeutic range, even at doses smaller than routine doses, for most patients. Additionally, CRP levels decreased more rapidly with the higher dose starting from 10 days after treatment initiation. The developed R Shiny application efficiently visualized the time courses of vancomycin and CRP concentrations, indicating its applicability in designing optimal treatment schemes simply based on visual inspection.
虽然万古霉素仍然是一种广泛使用的抗生素，但它可能会导致耳毒性和肾毒性，这两种毒性都与浓度相关。当治疗持续时间过长时，可能会出现过度治疗的情况。本研究采用模型指导的精准给药方案，旨在建立万古霉素的群体药代动力学（PK）和药效学（PD）模型，以确定最佳给药方案和治疗持续时间，从而避免药物诱导的毒性。数据来自542例患者的电子病历，其中包括40名儿童，并使用NONMEM软件进行分析。对于PK，万古霉素浓度采用包含异速生长标度的二室模型进行描述。结果显示，全身清除率随肌酐和血尿素氮水平、糖尿病和肾脏疾病史而降低，在女性中进一步降低。另一方面，中央分布容积随年龄增加。对于PD，C反应蛋白（CRP）血浆浓度通过转运室进行描述，发现其随肺炎的存在而降低。模拟结果表明，在模型指导的最佳剂量下，即使对于大多数患者而言剂量小于常规剂量，峰浓度、谷浓度以及浓度-时间曲线下面积仍保持在治疗范围内。此外，从治疗开始10天后，较高剂量使CRP水平下降得更快。所开发的R Shiny应用程序有效地可视化了万古霉素和CRP浓度的时间进程，表明其仅通过目视检查即可在设计最佳治疗方案中应用。
