IBMP Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany.
Antimicrob Agents Chemother. 2010 Mar;54(3):1275-82. doi: 10.1128/AAC.00936-09. Epub 2010 Jan 11.
Despite the promising activity of ceftazidime against Pseudomonas aeruginosa and Burkholderia cepacia, there has not yet been a study that directly compared the pharmacokinetics (PK) of ceftazidime in cystic fibrosis (CF) patients and healthy volunteers by population PK methodology. We assessed the population PK and PK/pharmacodynamic (PD) breakpoints of ceftazidime in CF patients and healthy volunteers. Eight CF patients (total body weight [WT] [average +/- standard deviation] = 42.9 +/- 18.4 kg) and seven healthy volunteers (WT = 66.2 +/- 4.9 kg) received 2 g ceftazidime as a 5-min intravenous infusion. High-performance liquid chromatography (HPLC) was used for drug analysis, and NONMEM (results reported), S-ADAPT, and NPAG were used for parametric and nonparametric population PK modeling. We considered linear and allometric body size models to scale clearance and volume of distribution. Monte Carlo simulations were based on a target time of non-protein-bound plasma concentration of ceftazidime above MIC of > or =65%, which represents near-maximal killing. Unscaled total clearance was 19% lower in CF patients, and volume of distribution was 36% lower. Total clearance was 7.82 liters/h for CF patients and 6.68 liters/h for healthy volunteers with 53 kg fat-free mass. Allometric scaling by fat-free mass reduced the between-subject variability by 32% for clearance and by 18 to 26% for volume of both peripheral compartments compared to linear scaling by WT. A 30-min ceftazidime infusion of 2 g/70 kg WT every 8 h (q8h) achieved robust (> or =90%) probabilities of target attainment (PTAs) for MICs of < or =1 mg/liter in CF patients and < or =3 mg/liter in healthy volunteers. Alternative modes of administration achieved robust PTAs up to markedly higher MICs of < or =8 to 12 mg/liter in CF patients for 5-h infusions of 2 g/70 kg WT q8h and < or =12 mg/liter for continuous infusion of 6 g/70 kg WT daily.
尽管头孢他啶对铜绿假单胞菌和洋葱伯克霍尔德菌具有良好的活性，但目前仍未有研究采用群体药代动力学方法直接比较囊性纤维化（CF）患者和健康志愿者体内头孢他啶的药代动力学（PK）。本研究旨在评估 CF 患者和健康志愿者体内头孢他啶的群体 PK 和 PK/药效学（PD）折点。8 例 CF 患者（体重均数 ± 标准差 [WT] = 42.9 ± 18.4 kg）和 7 例健康志愿者（WT = 66.2 ± 4.9 kg）接受 2 g 头孢他啶 5 分钟静脉输注。采用高效液相色谱法（HPLC）进行药物分析，NONMEM（报告结果）、S-ADAPT 和 NPAG 用于参数和非参数群体 PK 建模。我们分别采用线性和体表面积比例模型来对清除率和分布容积进行体表面积比例校正。蒙特卡罗模拟基于非蛋白结合血浆头孢他啶浓度时间超过 MIC 的目标值（>或=65%），该浓度值可实现最大杀菌效果。CF 患者的未校正总清除率降低 19%，分布容积降低 36%。CF 患者的总清除率为 6.68 升/小时，健康志愿者的总清除率为 7.82 升/小时，且健康志愿者的体脂质量为 53 千克。与 WT 线性体表面积比例校正相比，以去脂体质量进行体表面积比例校正可分别使清除率和外周分布容积的个体间变异性降低 32%和 18%至 26%。对于 CF 患者（70 kg WT 每 8 小时给予 2 g 头孢他啶，q8h）和健康志愿者（70 kg WT 每 8 小时给予 2 g 头孢他啶，q8h），30 分钟 2 g/70 kg WT 输注方案可使 MIC 值<或=1 mg/L 时的目标浓度时间百分比（PTAs）>或=90%，MIC 值<或=3 mg/L 时的 PTAs 达到 100%。5 小时 2 g/70 kg WT q8h 输注和每日 6 g/70 kg WT 持续输注可使 CF 患者的 MIC 值高达<或=8 至 12 mg/L 时达到稳健的 PTAs，而 MIC 值高达<或=12 mg/L 时达到稳健的 PTAs。
