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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Safety and pharmacokinetics of IDX184, a liver-targeted nucleotide polymerase inhibitor of hepatitis C virus, in healthy subjects.
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Safety and pharmacokinetics of IDX184, a liver-targeted nucleotide polymerase inhibitor of hepatitis C virus, in healthy subjects.

机译：IDX184（丙型肝炎病毒的肝脏靶向核苷酸聚合酶抑制剂）在健康受试者中的安全性和药代动力学。

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摘要

IDX184 is a nucleotide prodrug designed to enhance formation in the liver of the active triphosphate of 2'-methylguanosine (2'-MeG), a potent and specific polymerase inhibitor of the hepatitis C virus (HCV). In the present study, single ascending oral doses of 5, 10, 25, 50, 75, and 100 mg IDX184 were administered sequentially to cohorts of 8 healthy subjects, randomized 6:2, active/placebo. Plasma and urine pharmacokinetic sampling was performed over a period of 120 h after dosing. Upon absorption, IDX184 rapidly disappeared from plasma, with a mean half-life (t(1/2)) of approximately 1 h, while plasma concentrations of 2'-MeG gradually increased. Consistent with a liver-targeting approach, plasma exposure of IDX184 and 2'-MeG was low and was also dose related: the mean maximum concentrations ranged from 1.1 to 17 ng/ml for IDX184 and 1.7 to 19 ng/ml for 2'-MeG, and the respective mean total area under the curve ranged from 1.2 to 22.7 and 17.3 to 334 ng.h/ml. Mean 2'-MeG plasma concentrations 24 h after dosing were 0.6 to 3 ng/ml for the 25- to 100-mg doses. Mean 2'-MeG t(1/2) values ranged from 18 to 43 h for doses of 25 mg and above. Mean cumulative urine excretion was 0.2% and 12 to 20% of administered doses for the unchanged IDX184 and 2'-MeG, respectively. IDX184 was safe and well tolerated; no serious adverse events (SAEs), dose-dependent adverse events (AEs), or dose-limiting toxicities were observed. The incidence of AEs and laboratory abnormalities was low and was similar among subjects receiving IDX184 or a placebo. All AEs were mild to moderate and resolved at the end of study. The favorable safety and pharmacokinetic profiles support further clinical evaluation of IDX184 in HCV-infected patients.
机译：IDX184是一种核苷酸前药，旨在增强肝脏中2'-甲基鸟苷（2'-MeG）的活性三磷酸的形成，这是丙型肝炎病毒（HCV）的一种有效且特异性的聚合酶抑制剂。在本研究中，对8位健康受试者（随机6：2，活性药物/安慰剂）依次给药5、10、25、50、75和100 mg IDX184的单次递增口服剂量。给药后120小时内进行血浆和尿液药物动力学采样。吸收后，IDX184从血浆中迅速消失，平均半衰期（t（1/2））约为1小时，而2'-MeG的血浆浓度逐渐增加。与肝脏靶向方法一致，IDX184和2'-MeG的血浆暴露水平低，并且与剂量相关：IDX184的平均最大浓度范围为1.1至17 ng / ml，2'-的平均最大浓度范围为1.7至19 ng / ml MeG和曲线下各自的平均总面积在1.2到22.7和17.3到334 ng.h / ml之间。给药后24小时的平均2'-MeG血浆浓度为25至100 mg剂量为0.6至3 ng / ml。 25毫克及以上剂量的2'-MeG t（1/2）平均平均值介于18至43小时之间。对于不变的IDX184和2'-MeG，平均累积尿排泄分别为给药剂量的0.2％和12％至20％。 IDX184安全且耐受良好;没有观察到严重的不良事件（SAEs），剂量依赖性不良事件（AEs）或剂量限制性毒性。 AEs和实验室异常的发生率较低，并且在接受IDX184或安慰剂的受试者中相似。所有不良事件均为轻度至中度，并在研究结束时消退。良好的安全性和药代动力学特征支持IDX184在HCV感染患者中的进一步临床评估。

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