Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Department of Clinical Pharmacy, Antonius Hospital, Sneek, The Netherlands.
Clin Pharmacokinet. 2024 Jan;63(1):79-91. doi: 10.1007/s40262-023-01324-5. Epub 2023 Nov 16.
The latest vancomycin guideline recommends area under the curve (AUC)-targeted dosing and monitoring for efficacy and safety. However, guidelines for AUC-targeted starting dosing in patients with obesity and/or renal insufficiency are currently lacking. This study quantifies the pharmacokinetics (PK) of vancomycin in this population and provides AUC-targeted dosing recommendations.
Vancomycin concentrations (n = 1188) from therapeutic drug monitoring of 210 overweight and obese patients with varying degrees of renal (dys)function from the ward (74.8%) and intensive care unit (ICU, 25.2%) were pooled with published rich concentration-time data (n = 207) from 20 (morbidly) obese subjects undergoing bariatric surgery. A population model was developed using NONMEM 7.4. Stochastic simulations were performed to design dosing guidelines targeting an AUC between 400-600 mg·h/L.
Vancomycin clearance (CL) was found to increase linearly with total bodyweight and with renal function (CKD-EPI) in a power relation. Additionally, CL proved 15.5% lower in ICU patients. Our model shows that, to reach the target AUC between 400 and 600 mg·h/L in the first 48 h, two loading doses are required for both continuous infusion and intermittent dosing regimens. Maintenance doses were found to require adjustment for total bodyweight, renal function, and ICU admission status. With this guideline, the median AUC is well within the target from the start of the treatment onwards.
To achieve safe and effective vancomycin exposure for maintenance doses in overweight and obese patients, renal function, total bodyweight, and ICU admission status should be taken into account.
The AMIGO trial was registered in the Dutch Trial Registry [NTR6058].
最新的万古霉素指南建议针对疗效和安全性进行 AUC 靶向给药和监测。然而，目前缺乏针对肥胖和/或肾功能不全患者 AUC 靶向起始剂量的指南。本研究量化了该人群中万古霉素的药代动力学（PK），并提供了 AUC 靶向给药建议。
从病房（74.8%）和重症监护病房（ICU，25.2%）的 210 名超重和肥胖患者的治疗药物监测中汇总了万古霉素浓度（n=1188），这些患者的肾功能（异常）程度不同，并与发表的 20 名（病态）肥胖接受减肥手术的受试者的丰富浓度-时间数据（n=207）进行了合并。使用 NONMEM 7.4 开发了一个群体模型。进行随机模拟以设计靶向 AUC 在 400-600mg·h/L 之间的给药指南。
发现万古霉素清除率（CL）与体重和肾功能（CKD-EPI）呈线性关系，呈幂函数关系。此外，ICU 患者的 CL 低 15.5%。我们的模型表明，为了在 48 小时内达到 400-600mg·h/L 的目标 AUC，连续输注和间歇性给药方案都需要两种负荷剂量。发现维持剂量需要根据体重、肾功能和 ICU 入院状态进行调整。使用该指南，从中开始治疗开始，中位数 AUC 就在目标范围内。
为了在超重和肥胖患者中实现维持剂量的安全有效的万古霉素暴露，应考虑肾功能、体重和 ICU 入院状态。
AMIGO 试验在荷兰试验注册中心（NTR6058）注册。
