National Drug Information and Adverse Drug Reaction Monitoring Center, Hanoi University of Pharmacy, Hanoi, Vietnam.
National Drug Information and Adverse Drug Reaction Monitoring Center, Hanoi University of Pharmacy, Hanoi, Vietnam.
Int J Antimicrob Agents. 2019 Dec;54(6):702-708. doi: 10.1016/j.ijantimicag.2019.09.018. Epub 2019 Oct 7.
Despite extensive clinical use, limited data are available on optimal loading and maintenance doses of vancomycin in critically ill patients. This study aimed to develop a rational approach for optimised dosage of vancomycin given in a continuous infusion in critically ill patients.
Vancomycin pharmacokinetic (PK) data (total serum concentrations) were obtained from 55 intensive care unit (ICU) patients (Bach Mai Hospital, Hanoi, Vietnam) receiving a 20 mg/kg loading dose followed by continuous infusion stratified by creatinine clearance (CLCr). Population PK modelling and Monte Carlo simulations were performed using a nonlinear mixed-effects modelling (NONMEM) program for a target of 20-30 mg/L to optimise efficacy and minimise nephrotoxicity.
A two-compartment model with first-order elimination best fitted the PK data with central and peripheral volumes of distribution of 1.01 and 2.39 L/kg, respectively (allometric scaling to a 70 kg standard subject). The population total clearance of 3.63 L/h was only explained by renal function in the covariate and final model. The simulations showed that a 25-mg/kg loading dose infused over 90 minutes was optimal to reach the target range. The optimal maintenance dose for low renal function (CLCr < 45 mL/min) was 1000-1500 mg/day. For augmented renal clearance (CLCr > 130 mL/min) the dose should be up to 3500 mg/day or even 4500 mg/day to achieve adequate exposure. These simulated maintenance doses were larger than previously proposed for non-ICU patients.
Large loading and maintenance doses of vancomycin are generally needed in critically ill patients. Because of high interindividual variability in vancomycin PK, drug monitoring may still be necessary.
尽管万古霉素在临床上广泛应用，但关于危重患者最佳负荷剂量和维持剂量的数据有限。本研究旨在为危重患者连续输注万古霉素的优化剂量提供一种合理的方法。
从 55 名接受 20mg/kg 负荷剂量后按肌酐清除率（CLCr）分层的重症监护病房（ICU）患者（越南河内白梅医院）中获得万古霉素药代动力学（PK）数据（总血清浓度）。使用非线性混合效应模型（NONMEM）程序进行群体 PK 建模和蒙特卡罗模拟，目标浓度为 20-30mg/L，以优化疗效并最大程度减少肾毒性。
PK 数据最佳拟合为具有一级消除的两室模型，中央和外周分布容积分别为 1.01 和 2.39L/kg（按 70kg 标准体进行体表面积标化）。人群总清除率为 3.63L/h，仅通过协变量和最终模型中的肾功能解释。模拟结果表明，90 分钟内输注 25mg/kg 的负荷剂量是达到目标范围的最佳选择。对于低肾功能（CLCr<45mL/min），最佳维持剂量为 1000-1500mg/天。对于增强的肾清除率（CLCr>130mL/min），剂量应高达 3500mg/天甚至 4500mg/天，以达到足够的暴露。这些模拟的维持剂量大于以前提出的非 ICU 患者的剂量。
危重患者通常需要大剂量的万古霉素负荷剂量和维持剂量。由于万古霉素 PK 的个体间变异性很大，可能仍需要药物监测。
