Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, Health and Family Planning Commission, Shanghai, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
Xishan People's Hospital of Wuxi City, Jiangsu, China.
Clin Ther. 2018 Sep;40(9):1548-1555. doi: 10.1016/j.clinthera.2018.07.017. Epub 2018 Aug 23.
The pharmacokinetic (PK) and pharmacodynamic characteristics of levornidazole were studied in patients with intra-abdominal anaerobic infection to provide the rationale of new clinical dosing regimen of levornidazole.
A single-center, open, multidose trial was conducted in 16 patients with intra-abdominal anaerobic infection. Patients received levornidazole at 500mg q12h by intravenous infusion for 3 to 7days. The plasma samples collected before and after the last dose were analyzed by the LC-MS/MS method to determine the concentration of levornidazole. The PK parameters of levornidazole were calculated, and the PK profiles of levornidazole after the dosing regimen of 750mg q24h for 7days were simulated based on the linear PK profile of levornidazole. Monte Carlo simulation was used for estimating the cumulative fraction of response and probability of target attainment (PTA) of both dosing regimens at steady-state against Bacteroides fragilis.
After administration of the last dose of 500mg of levornidazole, the mean (SD) C, AUC, and t of levornidazole were 24.0 (5.37) μg/mL, 176.59 (29.22) μg·h/mL, and 11.03 (1.34) hours, respectively. The mean (SD) CL and V of levornidazole were 2.90 (0.47) L/h and 45.90 (7.44) L, respectively. The mean (SD) distribution volume of central compartment (V1) and distribution volume of peripheral compartment (V2) were 26.71 (8.51) L and 19.21 (10.86) L, respectively. On the basis of simulation, the accumulation ratio of levornidazole in the 750mg q24h dosing regimen was 30.2% lower than the value in the 500mg q12h dosing regimen. Forthe 2 dosing regimens, the C, AUC, AUC, CL, and V did not produce a significant difference between patients and healthy volunteers (P > 0.05). The cumulative fraction of response of levornidazole against B fragilis was >90%, and the probability of target attainment after both dosing regimens was >90%, when the MIC was ≤1 μg/mL.
No significant differences were found in the PK profiles of levornidazole at steady state between the patients with intra-abdominal anaerobic infection and healthy volunteers. The clinical conventional 750mg q24h regimen can achieve similar clinical and microbiological efficacies against anaerobic in the patients after the 500mg q12h regimen.
研究左旋甲硝唑在腹腔内厌氧菌感染患者中的药代动力学（PK）和药效学特征，为左旋甲硝唑新的临床给药方案提供依据。
在 16 例腹腔内厌氧菌感染患者中进行了一项单中心、开放、多剂量试验。患者接受左旋甲硝唑 500mg，q12h 静脉滴注，持续 3-7 天。在最后一次给药前后采集血浆样本，采用 LC-MS/MS 法测定左旋甲硝唑的浓度。计算左旋甲硝唑的 PK 参数，并根据左旋甲硝唑的线性 PK 曲线模拟 750mg，q24h 给药方案 7 天后的 PK 曲线。采用蒙特卡罗模拟估算两种给药方案在稳态下对脆弱拟杆菌的累积反应分数和目标达成率（PTA）。
左旋甲硝唑最后一次给药 500mg 后，左旋甲硝唑的平均（SD）C、AUC 和 t 分别为 24.0（5.37）μg/mL、176.59（29.22）μg·h/mL 和 11.03（1.34）小时。左旋甲硝唑的平均（SD）CL 和 V 分别为 2.90（0.47）L/h 和 45.90（7.44）L。左旋甲硝唑中央室分布容积（V1）和外周室分布容积（V2）的平均（SD）分别为 26.71（8.51）L 和 19.21（10.86）L。基于模拟，750mg，q24h 给药方案中左旋甲硝唑的蓄积率比 500mg，q12h 给药方案低 30.2%。对于这两种给药方案，患者与健康志愿者之间左旋甲硝唑的 C、AUC、AUC、CL 和 V 无显著差异（P>0.05）。当 MIC≤1μg/mL 时，左旋甲硝唑对脆弱拟杆菌的累积反应分数>90%，两种给药方案的目标达成率>90%。
腹腔内厌氧菌感染患者与健康志愿者在左旋甲硝唑稳态时的 PK 特征无显著差异。在接受 500mg，q12h 方案治疗后，临床常规的 750mg，q24h 方案可达到类似的临床和微生物学疗效。
