Guo Beining, He Gaoli, Wu Xiaojie, Yu Jicheng, Cao Guoying, Li Yi, Fan Yaxin, Chen Yuancheng, Shi Yaoguo, Zhang Yingyuan, Zhang Jing
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China.
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China.
Clin Ther. 2017 Jul;39(7):1336-1346. doi: 10.1016/j.clinthera.2017.05.350. Epub 2017 Jun 12.
Levornidazole, the levo-isomer of ornidazole, is a third-generation nitroimidazole derivative newly developed after metronidazole, tinidazole, and ornidazole. An open-label, parallel-controlled, single-dose study was conducted for the investigation of the pharmacokinetic (PK) profile of levornidazole and its metabolites in healthy elderly Chinese subjects, and for the evaluation of 2 dosing regimens in the elderly.
Levornidazole was intravenously administered at 500 mg to healthy elderly (aged 60-80 years) or young subjects (aged 19-45 years). The PK profiles of levornidazole and its metabolites in elderly subjects were evaluated and compared with those in the young group. WinNonlin software was used for simulating the PK profile of levornidazole in the elderly population following the dosing regimens of 500 mg BID and 750 mg once daily for 7 days. Monte Carlo simulation was used for estimating the cumulative fraction of response and probability of target attainment of both dosing regimens against Bacteroides spp.
The C, AUC and AUC values of levornidazole in the elderly group were 11.98 μg/mL, 131.36 μg·h/mL, and 173.61 μg·h/mL, respectively. The t, CL, and mean residence time from time 0 to infinity were 12.21 hours, 2.91 L/h, and 16.46 hours. The metabolic ratios of metabolites (M) 1, 2, 4, and 6 were <3.0%, and that of M16 was 17.70%. The urinary excretion values of levornidazole, M1, M2, M4, M6, and M16 over 96 hours were 10.21%, 0.92%, ~0%, 2.69%, 0.54%, and 41.98%. The PK properties of levornidazole and the urinary excretion of all metabolites were not statistically different between the 2 groups. The cumulative fraction of response was >90% against B fragilis and other Bacteroides spp, and the probability of target attainment was >90% when the minimum inhibitory concentration was ≤1 μg/mL, in both groups.
No dosing regimen adjustment is suggested when levornidazole is used in elderly patients with normal hepatic functioning and mild renal dysfunction. The findings from the PK/PD analysis imply that both regimens may achieve satisfactory clinical and microbiological efficacy against anaerobic infections in elderly patients. Chinese Clinical Trial Registry (http://www.chictr.org.cn) identifier: ChiCTR-OPC-16007938.
左奥硝唑是奥硝唑的左旋异构体，是继甲硝唑、替硝唑和奥硝唑之后新开发的第三代硝基咪唑衍生物。开展了一项开放标签、平行对照、单剂量研究，以调查左奥硝唑及其代谢产物在健康老年中国受试者中的药代动力学（PK）特征，并评估老年患者的两种给药方案。
将500mg左奥硝唑静脉注射给健康老年（60 - 80岁）或年轻受试者（19 - 45岁）。评估老年受试者中左奥硝唑及其代谢产物的PK特征，并与年轻组进行比较。使用WinNonlin软件模拟左奥硝唑在老年人群中按照500mg每日两次和750mg每日一次给药方案连续7天的PK特征。采用蒙特卡洛模拟估计两种给药方案针对拟杆菌属的反应累积分数和达标概率。
老年组中左奥硝唑的Cmax、AUC0 - t和AUC0 - ∞值分别为11.98μg/mL、131.36μg·h/mL和173.61μg·h/mL。从时间0到无穷大的t1/2、CL和平均驻留时间分别为12.21小时、2.91L/h和16.46小时。代谢产物（M）1、2、4和6的代谢率<3.0%，M16的代谢率为17.70%。左奥硝唑、M1、M2、M4、M6和M16在96小时内的尿排泄值分别为10.21%、0.92%、~0%、2.69%、0.54%和41.98%。两组之间左奥硝唑的PK特性和所有代谢产物的尿排泄在统计学上无差异。两组中针对脆弱拟杆菌和其他拟杆菌属的反应累积分数均>90%，当最低抑菌浓度≤1μg/mL时达标概率>90%。
对于肝功能正常和轻度肾功能不全的老年患者，使用左奥硝唑时不建议调整给药方案。PK/PD分析结果表明，两种给药方案对老年患者的厌氧菌感染均可能达到满意的临床和微生物学疗效。中国临床试验注册中心（http://www.chictr.org.cn）标识符：ChiCTR - OPC - 16007938。
