Li Caizheng, Sun Jiayu, Miao Jia, Qin Yongping, Wang Ying, Yu Rujia, Xiao Yonghong
a Institute of Clinical Pharmacology , West China Hospital, Sichuan University , Chengdu , China.
b Department of Infectious Diseases , West China Hospital, Sichuan University , Chengdu , China.
J Chemother. 2016 Jun;28(3):172-9. doi: 10.1179/1973947814Y.0000000214.
The objective of the study was to use Monte Carlo simulation to determine the optimal treatment dosing regimen of the cefetamet sodium for injection by analysing the pharmacokinetics (PK) parameters in healthy Chinese volunteers, and antibacterial activity in vitro was also examined. A three-cross Latin square single-dose PK study was designed. Twelve healthy volunteers were randomized to receive 500, 1000, and 2000 mg of cefetamet sodium for IV infusion over 30 minutes in three periods sequentially; and the washout time in between periods was 3 days. The drug concentrations in plasma were analysed by high-performance liquid chromatography, and the PK parameters were calculated using DAS2.0 PK software. The peak concentrations (Cmax) at 0.5 hours were 37.78±7.29, 76.18±12.81, and 149.32±29.94 mg/l, the areas under concentration-time curve (AUC0-t) were 69.75±14.44, 139.06±22.62, and 278.54±53.12 mg h/l, and the elimination half-life (t1/2) were 1.69±0.19, 1.69±0.27, and 1.81±0.23 hours for 500, 1000, and 2000 mg of cefetamet sodium for injection, respectively. The disposition of cefetamet was appear to fit a two-compartment model with linear kinetics. Antibacterial activity in vitro showed that most Gram-negative bacteria, including non-extended-spectrum beta-lactamases (ESBL)-producing Enterobacter, Haemophilus influenzae, Moraxella catarrhalis, and Neisseria gonorrhoeae, were sensitive to cefetamet. The result of Monte Carlo simulation showed that the probability of target attainment for bactericidal response (%fT>MIC≧50%) for susceptible bacteria was reached at all three dosing regimens of 500 mg, q6h, 1000 and 2000 mg, q8h and q6h. Considering the efficacy, safety, and pharmacoeconomy comprehensively, we recommended the dosing regimen of 500 mg, q6h for further clinical treatment based on the principle of minimum daily dosage.
本研究的目的是通过分析健康中国志愿者的药代动力学（PK）参数，使用蒙特卡洛模拟法确定注射用头孢他美钠的最佳治疗给药方案，并检测其体外抗菌活性。设计了一项三交叉拉丁方单剂量PK研究。12名健康志愿者被随机分为三组，在三个时间段内依次接受500、1000和2000mg注射用头孢他美钠静脉输注30分钟；各时间段之间的洗脱期为3天。采用高效液相色谱法分析血浆中的药物浓度，并使用DAS2.0 PK软件计算PK参数。500、1000和2000mg注射用头孢他美钠在0.5小时时的峰浓度（Cmax）分别为37.78±7.29、76.18±12.81和149.32±29.94mg/l，浓度-时间曲线下面积（AUC0-t）分别为69.75±14.44、139.06±22.62和278.54±53.12mg·h/l，消除半衰期（t1/2）分别为1.69±0.19、1.69±0.27和1.81±0.23小时。头孢他美的处置似乎符合具有线性动力学的二室模型。体外抗菌活性表明，大多数革兰氏阴性菌，包括产非超广谱β-内酰胺酶（ESBL）的肠杆菌、流感嗜血杆菌、卡他莫拉菌和淋病奈瑟菌，对头孢他美敏感。蒙特卡洛模拟结果表明，在500mg、q6h、1000mg和2000mg、q8h和q6h这三种给药方案下，敏感菌达到杀菌反应的目标达成概率（%fT>MIC≧50%）均能实现。综合考虑疗效、安全性和药物经济学，我们基于每日最小剂量原则，推荐500mg、q6h的给药方案用于进一步的临床治疗。
