德拉沙星在中国健康受试者中药代动力学/药效学研究  

Pharmacokinetics/pharmacodynamic study of delafloxacin in Chinese healthy subjects

作　　者：朱旭 卞星晨 郁继诚[1] 王晶晶[1] 杨海静[1] 曹国英[1] 武晓捷[1] 张菁[1] 陈昱竹 卢春林 宣景安[3] ZHU Xu;BIAN Xing-chen;YU Ji-cheng;WANG Jing-jing;YANG Hai-jing;CAO Guo-ying;WU Xiao-jie;ZHANG Jing;CHEN Yu-zhu;LU Chun-lin;XUAN Jing-an(Clinical Pharmacology Research Center,Huashan Hospital,Fudan University,Shanghai 200040,China;Clinical Center of The Pharmaceutical Research Institute,Yangtze River PharmaceuticlaGl roup Co.,Ltd.,Shanghai 201203,China;National Key Laboratory of Complex Drug Formulations for Overcoming Delivery Barriers,Yangtze River Pharmaceutical Group Co.,Ltd,Taizhou 225321,Jiangsu Province,China)

机构地区：[1]复旦大学附属华山医院临床药理研究中心,上海200040 [2]扬子江药业集团有限公司药物研究院临床中心,上海201203 [3]扬子江药业集团有限公司克服递药屏障高端制剂全国重点实验室,江苏泰州225321

出　　处：《中国临床药理学杂志》2025年第3期387-392,共6页The Chinese Journal of Clinical Pharmacology

基　　金：国家自然科学基金面上基金资助项目(82173896);上海申康医院发展中心研究型医师创新转化能力培训基金资助项目(SHDC2022CRS004B)。

摘　　要：目的评价氟喹诺酮类新药德拉沙星在中国健康受试者中药代动力学特征以及安全性,并通过药代动力学/药效学分析评价德拉沙星治疗金黄色葡萄球菌和肺炎链球菌所致感染的预期微生物学疗效。方法本试验分为2部分,第1部分为随机、双盲、安慰剂对照、单剂、多剂给药试验,给药剂量为150~450 mg,第2部分为随机、开放、双周期、自身交叉对照试验,比较静脉输注受试制剂和参比制剂300 mg的药代动力学相似性。结合德拉沙星对中国临床分离金黄色葡萄球菌和肺炎链球菌的体外药效学数据,以蒙特卡罗模拟法分析300 mg q12 h静脉输注60 min给药方案的达标概率及累积响应百分率,评价该方案的预期微生物学疗效。结果单剂给予中国健康成年受试者国产注射用德拉沙星150、300和450 mg后,C_(max)、AUC_(0-t)和AUC_(0-∞)随剂量成比例增加,表观分布容积高达45.79~144.38 L,各剂量组消除半衰期不等,在2.99~11.87 h。72 h内德拉沙星300和450 mg单剂给药累积尿排出率分别达到(47.69±8.11)%和(73.71±9.32)%,提示肾为主要排泄途径。德拉沙星受试制剂与参比制剂单剂静脉输注给药后的C_(max)、AUC_(0-t)和AUC_(0-∞)比值的90%置信区间均在80.00%~125.00%。300 mg组多剂给药达稳态后,血浆暴露水平与单剂给药组相近。结论健康受试者单剂静脉输注德拉沙星150~450 mg呈线性药代动力学特征,300 mg q12 h给药无蓄积,受试者药物不良反应轻微,安全性好,且可以获得良好的微生物学疗效。Objective To evaluate the pharmacokinetic characteristics and safety of delafloxacin,a new fluoroquinolone drug,in Chinese healthy subjects,and to evaluate the expected microbiological efficacy of delafloxacin in treating infections caused by Staphylococcus aureus and Streptococcus pneumoniae through pharmacokinetic/pharmacodynamic analysis.Methods This trial consists of two parts.The first part is a randomized,double-blind,placebo-controlled,single-dose/multiple-dose administration trial with a dose range of 150-450 mg.The second part is a randomized,open-label,double-period,self-crossover trial comparing the pharmacokinetic similarities between a 300 mg intravenous infusion of the test drug and the reference drug.Combined with the in vitro pharmacodynamic data of delafloxacin against Staphylococcus aureus and Streptococcus pneumoniae clinically isolated in China,the Monte Carlo simulation method was used to analyze the probability of target attainment and cumulative fraction of response of the 300 mg q12 h intravenous infusion over 60 min and to evaluate the expected microbiological efficacy.Results After administering 150,300 and 450 mg of delafloxacin to Chinese healthy subjects in single doses,the C_(max),AUC_(0-t)and AUC_(0-∞)increase proportionally with the dose.The apparent volume of distribution ranged from 45.79 to 144.38L.The elimination half-life of each dose group ranged from 2.99 to 11.87 h.The cumulative urinary excretion rates of(47.69±8.11)%and(73.71±9.32)%were observed for single doses of 300 and 450 mg,respectively,suggesting that the primary route of excretion was renal.The 90%confidence interval of C_(max),AUC_(0-t)and AUC_(0-∞)of test drug over reference drug after single-dose intravenous infusion are all within 80.00%-125.00%.After reaching steady state with multiple-dose administration in the 300 mg group,the plasma exposure level was similar to that of the single-dose administration group.Conclusion Single-dose intravenous infusion of 150-450 mg delafloxacin in healthy subjects show

关 键 词：德拉沙星 抗菌药物 药代动力学/药效学 安全性 

分 类 号：R978.1[医药卫生—药品]