在健康中国志愿者中静脉注射氟比洛芬氨丁三醇的药代动力学、安全性和耐受性：一项首次人体单剂量和多剂量递增 I 期研究，采用随机、双盲、安慰剂对照设计。
Pharmacokinetics, Safety, and Tolerability of Intravenous Felbinac Trometamol in Healthy Chinese Volunteers: A First-in-Human Single- and Multiple-Dose Escalation Phase I Study with a Randomized, Double-Blind, Placebo-Controlled Design.
机构信息
Department of Phase I Clinical Trial Unit, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
Shijiazhuang Yiling Pharmaceutical Co., Ltd, Shijiazhuang, 050035, Hebei, China.
出版信息
CNS Drugs. 2020 Aug;34(8):867-877. doi: 10.1007/s40263-020-00739-z.
BACKGROUND
Felbinac trometamol, an anti-inflammatory and analgesic drug, has been used to treat immediate postoperative pain.
OBJECTIVE
The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics of single or multiple intravenous infusions of felbinac trometamol in healthy Chinese volunteers.
METHODS
A total of 56 healthy subjects were enrolled in a single-ascending dose study (11.78-377.00 mg), meanwhile 36 subjects were enrolled in a multiple-ascending dose study (47.13-188.50 mg). Safety endpoints included treatment-emergent adverse events, vital signs, electrocardiograms, and laboratory parameters. Pharmacokinetic endpoints included exposure of subjects to felblinac and metabolites of the drug in plasma, urine, and feces.
RESULTS
Felblinac time to maximum plasma concentration was obtained at 0.5 h, corresponding to the end of the infusion. Maximum plasma concentration and area under the curve increased in a dose-dependent manner for felblinac and its metabolite, showing linear pharmacokinetic characteristics at single and multiple doses. After intravenous infusions of multiple doses three times (30 min each time) per day, the accumulation ratio of felblinac and its metabolite based on the area under the curve had a range of 1.34-1.45 and 1.60-1.87, respectively, across cohorts. After administration of the fourth dose, the plasma concentration of both felblinac and its metabolites was maintained at a steady state. Felbinac trometamol was well tolerated. Neither treatment-emergent adverse event frequency nor severity increased with increasing felbinac trometamol dose.
CONCLUSIONS
Felbinac trometamol was well tolerated in our study. Based on the dose range in this study, 94.25 mg is the recommended target dose for a phase II study.
CLINICAL TRIAL REGISTRATION
CTR20170496 and CTR20180896. The dates of registration are 2017-06-19 and 2018-07-02 ( https://www.chinadrugtrials.org.cn/ ).
背景
非甾体类抗炎药和镇痛药氟比洛芬氨丁三醇已被用于治疗术后即刻疼痛。
目的
本研究旨在评估健康中国志愿者单次和多次静脉输注氟比洛芬氨丁三醇的安全性、耐受性和药代动力学。
方法
共纳入 56 名健康受试者进行单次递增剂量研究（11.78-377.00mg），同时纳入 36 名受试者进行多次递增剂量研究（47.13-188.50mg）。安全性终点包括治疗后出现的不良事件、生命体征、心电图和实验室参数。药代动力学终点包括氟比洛芬及其代谢物在血浆、尿液和粪便中的暴露量。
结果
氟比洛芬氨丁三醇达峰时间为 0.5h，即输注结束时。氟比洛芬及其代谢物的最大血浆浓度和曲线下面积随剂量呈依赖性增加，单次和多次剂量均表现出线性药代动力学特征。每天静脉输注 3 次（每次 30min），基于曲线下面积的氟比洛芬及其代谢物的蓄积比在各队列中分别为 1.34-1.45 和 1.60-1.87。给予第 4 剂后，氟比洛芬及其代谢物的血浆浓度均维持在稳态。氟比洛芬氨丁三醇耐受性良好。氟比洛芬氨丁三醇剂量增加，治疗后不良事件的发生频率和严重程度均无增加。
结论
本研究中，氟比洛芬氨丁三醇耐受良好。基于本研究的剂量范围，94.25mg 是 II 期研究的推荐目标剂量。
临床试验注册
CTR20170496 和 CTR20180896。注册日期为 2017 年 6 月 19 日和 2018 年 7 月 2 日（https://www.chinadrugtrials.org.cn/）。
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