庆大霉素在癌症患者中的群体药代动力学。
Population pharmacokinetics of gentamicin in patients with cancer.
作者信息
Rosario M C, Thomson A H, Jodrell D I, Sharp C A, Elliott H L
机构信息
University Department of Medicine and Therapeutics, West Glasgow Hospitals University NHS Trust.
出版信息
Br J Clin Pharmacol. 1998 Sep;46(3):229-36. doi: 10.1046/j.1365-2125.1998.00779.x.
AIMS
The purpose of this study was to describe the population pharmacokinetics of gentamicin in patients with cancer, to identify possible relationships between clinical covariates and population pharmacokinetic parameter estimates and to examine the relevance of existing dosage nomograms in light of the population model developed in these patients.
METHODS
Data were collected prospectively from 210 patients with cancer and were analysed with package NONMEM. Data were split into two sets: a population data set and an evaluation set. Creatinine clearance was estimated using measured creatinine concentrations and using 'low' creatinines set to a minimum of 60 micromol l(-1), 70 micromol l(-1) or 88.4 micromol l(-1)
RESULTS
A two compartment model was fitted to the concentration-time curve. Two best models were obtained, one that related clearance to estimated creatinine clearance (minimum creatinine value 60 micromol l(-1)) and the other that related clearance to age, creatinine concentration and body surface area. Volume of the central compartment was influenced by body surface area and albumin concentration. For both models 90% of measured concentrations lay within the 95% confidence interval of the simulated concentrations and the mean prediction errors were -7.2% and -6.6%, respectively. A final analysis performed in all patients identified the following relationship CL (1 h(-1))=0.88 x (1 + 0.043 x creatinine clearance) and central volume of distribution V1 (1)=8.59 x body surface area x (albumin/34)(-0.39). The mean population estimate of intercompartmental clearance (Q) was 1.301 h(-1) and peripheral volume of distribution (V2) was 9.801. Coefficient of variation was 18.5% on clearance and 28.2% on Q. Residual error expressed as a standard deviation was 0.36 mg l(-1) at 1.0 mg l(-1) and 1.32 mg l(-1) at 8.0 mg l(-1). The mean population estimate of clearance was 4.21 h(-1) and volume of distribution (Vss) was 24.61 (0.381 kg(-1)). The mean population estimates of half-lives were 1.8 h and 8.0 h.
CONCLUSIONS
In the context of published nomograms this analysis indicated that both the traditional approach and the new, 'once daily' approach should achieve satisfactory concentrations in cancer patients although serum concentration monitoring is required to confirm optimal dosing in individual patients.
目的
本研究旨在描述庆大霉素在癌症患者中的群体药代动力学，确定临床协变量与群体药代动力学参数估计值之间的可能关系，并根据在这些患者中建立的群体模型检验现有剂量线图的相关性。
方法
前瞻性收集210例癌症患者的数据，并用NONMEM软件包进行分析。数据分为两组：群体数据集和评估集。使用测量的肌酐浓度以及设定为最低60 μmol/L、70 μmol/L或88.4 μmol/L的“低”肌酐值来估计肌酐清除率。
结果
用二室模型拟合浓度-时间曲线。获得了两个最佳模型，一个将清除率与估计的肌酐清除率相关联（最低肌酐值60 μmol/L），另一个将清除率与年龄、肌酐浓度和体表面积相关联。中央室容积受体表面积和白蛋白浓度影响。对于这两个模型，90%的测量浓度落在模拟浓度的95%置信区间内，平均预测误差分别为-7.2%和-6.6%。在所有患者中进行的最终分析确定了以下关系：CL（1 h⁻¹）=0.88×（1 + 0.043×肌酐清除率），中央分布容积V1（1）=8.59×体表面积×（白蛋白/34）⁻⁰.³⁹。室间清除率（Q）的群体平均估计值为1.301 h⁻¹，外周分布容积（V2）为9.801。清除率的变异系数为18.5%，Q的变异系数为28.2%。以标准差表示的残余误差在1.0 mg/L时为0.36 mg/L，在8.0 mg/L时为1.32 mg/L。清除率的群体平均估计值为4.21 h⁻¹，分布容积（Vss）为24.61（0.381 kg⁻¹）。半衰期的群体平均估计值为1.8 h和8.0 h。
结论
在已发表的剂量线图背景下，该分析表明，传统方法和新的“每日一次”方法在癌症患者中均应能达到满意的浓度，尽管需要监测血清浓度以确定个体患者的最佳给药剂量。
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