Chen M, Nafziger A N, Drusano G L, Ma L, Bertino J S
Clinical Pharmacology Research Center, The Research Institute, and Department of Medicine, Bassett Healthcare, Cooperstown, NY, USA.
Antimicrob Agents Chemother. 2006 Apr;50(4):1222-7. doi: 10.1128/AAC.50.4.1222-1227.2006.
Little is known of the effects of obesity on ertapenem drug disposition and pharmacodynamics. Thirty healthy volunteers in three body mass index (BMI) groups (10 per group), normal weight (BMI, 18.5 to 24.9 kg/m2), class I-II obesity (BMI, 30 to 39.9 kg/m2), and class III obesity (BMI, >or=40 kg/m2), were administered a 1-g dose of ertapenem. Serum concentrations were obtained over 24 h. Population pharmacokinetic data were obtained using a nonparametric adaptive grid followed by Monte Carlo simulation to determine the probability of obtaining the free drug exposure targets of the time that the free drug concentration remains above the MIC (fT>MIC) of 20% and 40% for bacteriostatic and maximal bactericidal activity, respectively. Compared to the subjects in the obese groups, area under the concentration-time curve from 0 h to infinity was significantly higher in the normal-weight subjects, whereas the total central compartment volume was higher in the class III obese subjects (P<or=0.05). Achieving a bacteriostatic target of fT>MIC of 20% with a 90% probability was attained at MICs of <or=0.5 microg/ml for normal-weight subjects. Class I-II and class III obese subjects were able to achieve this target only at a MIC of <or=0.25 microg/ml. For maximal bactericidal activity (fT>MIC, 40%), no group attained the target at the 90% probability level at any tested MIC. The results suggest that the standard 1-g ertapenem dose may not provide adequate drug exposure for any body mass index classification for MICs in excess of 0.25 to 0.5 microg/ml.
关于肥胖对厄他培南药物处置和药效学的影响，目前所知甚少。30名健康志愿者被分为三个体重指数（BMI）组（每组10人），分别为正常体重组（BMI，18.5至24.9kg/m²）、I-II级肥胖组（BMI，30至39.9kg/m²）和III级肥胖组（BMI，≥40kg/m²），均接受1g剂量的厄他培南。在24小时内获取血清浓度。使用非参数自适应网格，随后进行蒙特卡罗模拟以获得群体药代动力学数据，从而确定分别达到抑菌活性和最大杀菌活性时，游离药物浓度保持高于最低抑菌浓度（fT>MIC）20%和40%的游离药物暴露目标的概率。与肥胖组受试者相比，正常体重受试者从0小时至无穷大的浓度-时间曲线下面积显著更高，而III级肥胖受试者的中央室总体积更高（P≤0.05）。对于正常体重受试者，在最低抑菌浓度≤0.5μg/ml时，有90%的概率达到抑菌目标fT>MIC为20%。I-II级肥胖组和III级肥胖组仅在最低抑菌浓度≤0.25μg/ml时才能达到该目标。对于最大杀菌活性（fT>MIC，40%），在任何测试的最低抑菌浓度下，没有一组能在90%概率水平达到目标。结果表明，对于最低抑菌浓度超过0.25至0.5μg/ml的情况，标准的1g厄他培南剂量可能无法为任何体重指数分类提供足够的药物暴露。
