Clinical Pharmacokinetics of Meropenem and Biapenem in Bile and Dosing Considerations for Biliary Tract Infections Based on Site-Specific Pharmacodynamic Target Attainment
Clinical Pharmacokinetics of Meropenem and Biapenem in Bile and Dosing Considerations for Biliary Tract Infections Based on Site-Specific Pharmacodynamic Target Attainment
复制标题
DOI：
10.1128/aac.00497-11
复制
发表时间：
2011-12-01
影响因子：
4.9
通讯作者：
Sueda, Taijiro
中科院分区：
文献类型：
--
作者：
Ikawa, Kazuro;Nakashima, Akira;Sueda, Taijiro
本研究研究了美罗培南和比阿培南在胆汁中的药代动力学，并估计了它们在现场的药效学目标实现情况。手术患者给予美罗培南（0.5 g）或比阿培南（0.3 g）（每种药物n = 8）。在输注结束时（0.5 h）和输注后5 h采集静脉血和肝胆道胆汁样本。对血浆和胆汁中的药物浓度进行药代动力学分析，并使用蒙特卡罗模拟来预测达到药效学目标的概率（高于MIC的40%时间）。两种药物对胆汁的渗透相似，平均胆汁/血浆比值为0.24 ~ 0.25（最大药物浓度）和0.30 ~ 0.38（药物浓度-时间曲线下面积）。美罗培南（0.5 g / 8h [q8h]）和比阿培南（0.3 g / 8h） （0.5 h输注）的常规方案对大肠杆菌、肺炎克雷伯菌和阴沟肠杆菌分离株的胆汁达到目标的概率相似（>= 90%）。而对铜绿假单胞菌菌株，1 g / 8h的美罗培南和0.6 g / 8h的双阿培南的需用量分别为80.7%和71.9%。美罗培南的胆道药效学断点为0.5 g q8h为1 mg/升，1 g q8h为2 mg/升，比阿培南0.3 g q8h为0.5 mg/升，0.6 g q8h为1 mg/升。这些结果有助于确定两种碳青霉烯类药物在胆汁中的临床药代动力学，同时也有助于根据特定部位的药效学目标实现来合理化和优化胆道感染的给药方案。
The present study investigated the pharmacokinetics of meropenem and biapenem in bile and estimated their pharmacodynamic target attainment at the site. Meropenem (0.5 g) or biapenem (0.3 g) was administered to surgery patients (n = 8 for each drug). Venous blood samples and hepatobiliary tract bile samples were obtained at the end of infusion (0.5 h) and for up to 5 h thereafter. Drug concentrations in plasma and bile were analyzed pharmacokinetically and used for a Monte Carlo simulation to predict the probability of attaining the pharmacodynamic target (40% of the time above the MIC). Both drugs penetrated similarly into bile, with mean bile/plasma ratios of 0.24 to 0.25 (maximum drug concentration) and 0.30 to 0.38 (area under the drug concentration-time curve). The usual regimens of meropenem (0.5 g every 8 h [q8h]) and biapenem (0.3 g q8h) (0.5-h infusions) achieved similar target attainment probabilities in bile (>= 90%) against Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae isolates. However, against Pseudomonas aeruginosa isolates, meropenem at 1 g q8h and biapenem at 0.6 g q8h were required for values of 80.7% and 71.9%, respectively. The biliary pharmacodynamic-based breakpoint (the highest MIC at which the target attainment probability in bile was >= 90%) was 1 mg/liter for 0.5 g q8h and 2 mg/liter for 1 g q8h for meropenem and 0.5 mg/liter for 0.3 g q8h and 1 mg/liter for 0.6 g q8h for biapenem. These results help to define the clinical pharmacokinetics of the two carbapenems in bile while also helping to rationalize and optimize the dosing regimens for biliary tract infections based on site-specific pharmacodynamic target attainment.