Department of Medicine, Michigan State University, East Lansing, USA.
Ann Pharmacother. 2012 Oct;46(10):1281-6. doi: 10.1345/aph.1R097. Epub 2012 Sep 25.
Doripenem is a group 2 carbapenem with enhanced in vitro activity against gram-negative bacteria including Pseudomonas aeruginosa. There is a paucity of pharmacokinetic/pharmacodynamic data on doripenem in patients with febrile neutropenia.
To conduct a pharmacokinetic evaluation of 2 doses of doripenem in patients with febrile neutropenia and provide probability estimates of attaining effective drug exposure against common gram-negative pathogens.
We obtained multiple blood samples from 12 adults with febrile neutropenia who were receiving either 500 mg or 1000 mg of intravenous doripenem over 4 hours every 8 hours. Following at least 2 doses, serum concentrations were measured in each subject at 1, 4, 6, and 8 hours after initiation of a dose by a validated high-performance liquid chromatography assay. The derived pharmacokinetic parameters from these serum levels were used to perform a 5000-patient Monte Carlo simulation against bacteria with minimal inhibitory concentrations (MICs) of 0.008-64 mg/L to determine probability estimates of the time in which unbound drug concentrations remain above the MIC (fT(>MIC)).
The mean pharmacokinetic parameters in these patients were a volume of distribution of 43.9 L, an elimination rate constant of 0.37 h(-1), a total clearance of 14.4 L/h, and an area under the concentration-time curve of 57.6 mg•h/L. An optimal probability of target attainment (40% fT(>MIC)) of 90% was obtained against bacteria with MICs ≤2 mg/L and ≤4 mg/L with 500-mg and 1000-mg doses, respectively. Adverse events associated with doripenem were not observed.
The findings from this analysis of doripenem suggest that higher doses, as well as prolonged infusions, may be necessary to optimally treat selected gram-negative bacteria (eg, P. aeruginosa) in patients with febrile neutropenia.
多利培南是一种 2 类碳青霉烯类抗生素，对包括铜绿假单胞菌在内的革兰氏阴性菌具有增强的体外活性。在患有发热性中性粒细胞减少症的患者中，有关多利培南的药代动力学/药效学数据很少。
对发热性中性粒细胞减少症患者的两种剂量多利培南进行药代动力学评估，并提供针对常见革兰氏阴性病原体达到有效药物暴露的概率估计。
我们从 12 名接受静脉注射多利培南 500mg 或 1000mg 每 8 小时一次，每次 4 小时的发热性中性粒细胞减少症成人患者中获得了多个血样。在至少给予 2 剂后，通过验证的高效液相色谱法在每个患者中在剂量开始后 1、4、6 和 8 小时测量血清浓度。从这些血清水平得出的药代动力学参数用于对最小抑菌浓度（MIC）为 0.008-64mg/L 的细菌进行 5000 例患者蒙特卡罗模拟，以确定游离药物浓度高于 MIC（fT(>MIC)）的时间的概率估计。
这些患者的平均药代动力学参数为 43.9L 的分布容积、0.37h(-1)的消除率常数、14.4L/h 的总清除率和 57.6mg•h/L 的浓度-时间曲线下面积。对于 MIC≤2mg/L 和≤4mg/L 的细菌，500mg 和 1000mg 剂量的目标获得率（40%fT(>MIC)）分别为 90%，可获得最佳概率。未观察到与多利培南相关的不良事件。
这项对多利培南的分析发现，在发热性中性粒细胞减少症患者中，为了优化治疗某些革兰氏阴性菌（例如铜绿假单胞菌），可能需要更高的剂量和更长的输注时间。
