LBPT及其主要代谢产物的药代动力学，以及首次人体研究中的耐受性。
Pharmacokinetics of LBPT and its primary metabolites, as well as tolerability in the first-in-human study.
作者信息
Wang Hongyun, Liu Hongzhong, Liu Ming, Wang Wenjie, Zhu Liya, Huang Haihong, Hu Pei, Jiang Ji
机构信息
Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100730, China.
Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China.
出版信息
Eur J Pharm Sci. 2017 Mar 30;100:87-93. doi: 10.1016/j.ejps.2016.12.038. Epub 2017 Jan 3.
BACKGROUND
LBPT is a novel platelet-activating factor (PAF) receptor antagonist that is developed for the treatment of rheumatoid arthritis. The purpose of this first-in-human study was to evaluate the tolerability and safety of LBPT, to investigate the pharmacokinetics of LBPT and its primary metabolites, as well as to assess the food effect on the pharmacokinetics in healthy Chinese subjects.
MATERIALS AND METHODS
LBPT was evaluated in 2 clinical studies. The first study was a double blind, placebo-controlled and ascending dose study. Eighty-five healthy Chinese subjects received oral dose of 2, 4, 6, 8, 15, 25, 50, 75, 100, 125, 150, 225, 300, 400 or 500mg of LBPT or placebo. The pharmacokinetics of LBPT and its primary metabolites were investigated in the last 4 dose cohorts. The tolerability was evaluated by monitoring adverse events (AEs), physical examinations, 12-lead electrocardiograms (ECG) and laboratory tests. The second study was an open-label, 2-period cross-over study with a washout interval of 3days. Twelve subjects received 300mg of LBPT after an overnight fasting or a high-fat breakfast. The pharmacokinetics of LBPT in subjects under fasted and fed conditions were compared.
RESULTS
LBPT was well tolerated up to 500mg-dose and there were no serious AEs in the study. The incidence and severity of AEs were closely related to dose. Following single oral administration of 225, 300, 400 and 500mg of LBPT, plasma C was reached at 0.5h and the mean t was 0.6-1.6h. Plasma exposure increased with dose escalation but proportionality was not observed. LBPT was eliminated in forms of metabolites and 20-40% of the given dose was recovered in urine. Compared with the subjects under fasting conditions, AUC and C were lower and t was delayed in the fed subjects.
CONCLUSION
LBPT was well tolerated in healthy subjects with a pattern of dose-related AEs. The pharmacokinetics was non-linear and was impacted by food intake.
背景
LBPT是一种新型血小板活化因子（PAF）受体拮抗剂，用于治疗类风湿性关节炎。这项首次人体研究的目的是评估LBPT的耐受性和安全性，研究LBPT及其主要代谢产物的药代动力学，以及评估食物对健康中国受试者药代动力学的影响。
材料与方法
在2项临床研究中对LBPT进行了评估。第一项研究是一项双盲、安慰剂对照、剂量递增研究。85名健康中国受试者口服2、4、6、8、15、25、50、75、100、125、150、225、300、400或500mg的LBPT或安慰剂。在最后4个剂量组中研究了LBPT及其主要代谢产物的药代动力学。通过监测不良事件（AE）、体格检查、12导联心电图（ECG）和实验室检查来评估耐受性。第二项研究是一项开放标签、两期交叉研究，洗脱期为3天。12名受试者在空腹过夜或高脂早餐后接受300mg的LBPT。比较了禁食和进食条件下受试者LBPT的药代动力学。
结果
LBPT在高达500mg剂量时耐受性良好，研究中未出现严重不良事件。不良事件的发生率和严重程度与剂量密切相关。单次口服225、300、400和500mg的LBPT后，血浆C在0.5小时达到，平均t为0.6 - 1.6小时。血浆暴露量随剂量增加而增加，但未观察到比例关系。LBPT以代谢产物的形式消除，给药剂量的20 - 40%在尿液中回收。与禁食条件下的受试者相比，进食受试者的AUC和C较低，t延迟。
结论
LBPT在健康受试者中耐受性良好，不良事件与剂量有关。药代动力学呈非线性，受食物摄入影响。
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