的药代动力学和药效学评价dipeptidyl peptidase-4抑制剂PHX1149:双盲、安慰剂对照、单——multiple-dose在健康受试者的研究。

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奥法雷尔,van Vliet,阿布Farha K, Cherrington JM,坎贝尔哒,李X, Hanway D,李江,居尔惠普

的药代动力学和药效学评价dipeptidyl peptidase-4抑制剂PHX1149:双盲、安慰剂对照、单——multiple-dose在健康受试者的研究。

其他。2007年8月,29 (8):1692 - 705。

PubMed ID
17919550 (在PubMed
]
文摘

背景:PHX1149 dipeptidyl peptidase-4 (DPP4)抑制剂,目前在临床治疗2型糖尿病的发展。PHX1149很小(分子量= 241.16 Da),高度水溶性(> 2 g / mL),口服活性分子的选择性指数15 - 319倍,相对于其他民进党的家人。DPP4的生化抑制浓度中位数是2.5 nmol / L。目的:目的是这两双盲、随机、安慰剂对照的研究是研究药代动力学(PK)参数和药效学(PD)的属性和耐受性的单个和多个提升剂PHX1149在健康人体。方法:18到60岁的健康男性和女性被招募参加一个——或者multiple-dose顺序使用剂量升级模式的研究。在单剂研究中,受试者都被赋予了一项单一的口服剂量的PHX1149 50至500毫克或安慰剂;在multiple-dose研究中,受试者被要求在PHX1149剂量从50到400毫克或安慰剂QD 13天。没有intrasubject剂量升级。收集血液样本从每个主题的一系列时间点从1小时前1天给药后24小时在单剂量研究1天,7和13 multiple-dose研究。PK和PD分析血浆样品中确定Cmax,达峰时间,AUC0-t, AUC0-infinity, DPP4酶活性。 The drug accumulation index was also calculated for each dose of PHX1149 in the multiple-dose study. Adverse events (AEs) were monitored in both studies through physical examinations, including measurement of vital signs, and clinical laboratory testing. In both studies, electrocardiography was performed. RESULTS: The single- and multiple-dose studies enrolled 30 and 28 subjects, respectively, for a total enrollment in the 2 studies of 58 healthy adult subjects. The distribution of male and female subjects was 14 (47%) and 16 (53%), respectively, in the single- dose study and 16 (57%) and 12 (43%) in the multiple- dose study. In the single-dose study, 28 (93%) subjects were white; in the multidose study, all subjects were white. The mean (SD) ages in the 2 studies were 51 (10) and 51 (12) years, respectively; and mean (SD) body weights were 89.0 (10.8) and 81.1 (10.9) kg, respectively. PHX1149 exhibited dose-proportional increases in mean Cmax AUC0-t, and AUC0-infinity across the evaluated dose ranges. Tmax ranged from 2 to 4 hours, and t1/2 ranged from approximately 10 to 13 hours. No drug accumulation was observed. Plasma DPP4 inhibition at 24 hours was >or=50% in the multiple-dose study for doses of >or=100 mg. PHX1149 400 mg achieved approximately 90% 24-hour plasma DPP4 inhibition in the multiple-dose study. All AEs were characterized as mild, with the exception of 1 case of moderate edema, which occurred 17 days after the end of dosing in the multiple-dose study (50-mg dose group) and was considered unrelated to the study drug. Adverse events were experienced by 47% of all subjects studied in the single-dose study and 93% of subjects in the multiple-dose study. The rates of AEs were comparable between the study and placebo groups. CONCLUSIONS: The PK parameters and PD properties of PHX1149 were suitable (eg, tl/2, DPP4 inhibition) for once-daily dosing in this group of 58 healthy subjects. All doses were well tolerated.

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