注射用多尼培南健康人体药代动力学研究

目的 考察注射用多尼培南在中国健康人体单次给药的临床药代动力学特性，为临床推荐优化的治疗方案。方法 12例健康志愿者按拉丁方三交叉试验设计，随机先后单剂量静脉滴注多尼培南0.25、0.5、1.0 g，采用高效液相色谱法分离紫外检测法(HPLC-UV)测定人血浆及尿中多尼培南浓度。用Phoenix? WinNonlin?6.1药代动力学程序计算得到非房室模型统计矩参数，并进行药代动力学特征分析。结果 单次静脉滴注多尼培南0.25、0.5、1.0 g后，血药峰浓度（C_max）分别为（11.81±1.52）、（22.80±3.80）和（47.26±8.38） μg／mL；达峰时间（T_max）分别为（60.42±1.44）、（58.33±5.77）和（60.00±0） min；半衰期（t_1/2）分别为（63.48±10.51）、（69.12±16.72）和（69.30±11.71） min；药时曲线下面积（AUC_0～t）分别为（1 100.86±150.04）、（2 111.50±359.58）和（4 359.50±789.38） μg／（mL·min）。直线回归分析和置信区间法分析均提示本品具有线性药代动力学特征。本品主要经肾脏排泄，给药后24 h尿液累积排泄率为70%~75%。本品安全性较好，不良反应发生率为19.44%，均为轻度。结论 注射用多尼培南具有线性动力学特征，男女患者应用本品无需调整给药剂量。

Pharmacokinetics Study of Injected Doripenemin Healthy Volunteers

Objective To study the pharmacokinetics of injected doripenem in Chinese healthy volunteers, in order to optimize dosages for patients. Methods Twelve healthy volunteers were recruited in the three-cross Latin square designed study. Participants received intravenous infusions of 0.25, 0.5 and 1.0 g doripenem sequentially in three periods at a random order. Plasma and urine doripenem were measured by HPLC-UV, using an internal standard method with meropenem for plasma samples and an external standard method for urine samples, respectively. Phoenix?WinNonlin?6.1 pharmacokinetic software was used to calculate non-compartment pharmacokinetics parameters. SPSS 19.0 software was used for statistical analysis. Results A single dose infusion of 0.25, 0.5 and 1.0 g doripenemin 60 min produced the following respective parameters: Cmax (11.81±1.52), (22.80±3.80) and (47.26±8.38) μg/mL, Tmax (60.42±1.44), (58.33±5.77) and (60.00±0) min, t_1/2 (63.48±10.51), (69.12±16.72) and (69.30±11.71) min, AUC_0-t (1 100.86±150.04), (2 111.50±359.58) and (4 359.50±789.38) μg/(mL·min). Linear Regression and Confidence Interval analyses suggested a linear kinetic characteristic. Doripenem was mainly excreted through kidneys, with 24 h cumulative urine excretion rates ranging from 70% to 75% for the three doses of infusions. It was safe to administer doripenem through infusion in healthy volunteers. Adverse reactions occurred in 19.44%cases of infusions, although all were mild reactions. Tinnitus happened in two cases (8.33%) of infusions, which required close observations. Conclusion Doripenem infusion possesses a linear kinetics. There is no need to adjust the regimenpatients.