一项随机，双盲，安慰剂对照，首次人体研究，用于评估GSK33

StephenW

Clin Pharmacol Drug Dev. 2019 Mar 12. doi: 10.1002/cpdd.670. [Epub ahead of print]
A Randomized, Double-Blind, Placebo-Controlled, First-Time-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects.
Han K1, Cremer J2, Elston R3, Oliver S4, Baptiste-Brown S1, Chen S1, Gardiner D1, Davies M5, Saunders J1, Hamatake R2, Losos J2, Leivers M2, Hood S3, van der Berg F6, Paff M7, Ritter JM8, Theodore D2.
Author information
Abstract

GSK3389404 is a liver-targeted antisense oligonucleotide that inhibits synthesis of hepatitis B surface antigen and all other hepatitis B virus proteins. This first-in-human, randomized, double-blind, phase 1 study assessed the safety and pharmacokinetics of GSK3389404 administered subcutaneously (SC) in healthy subjects. Four single ascending-dose cohorts (10 mg, 30 mg, 60 mg, and 120 mg) and 3 multiple ascending-dose cohorts (30 mg, 60 mg, and 120 mg once weekly for 4 weeks) each comprised 6 subjects randomized to GSK3389404 and 2 subjects randomized to placebo. There were no serious adverse events (AEs) or withdrawals due to AEs. The safety profile did not worsen with repeated dosing. The most frequent treatment-related AEs were injection site reactions (19.0% [n = 8/42], frequency unrelated to dose levels); all were mild (Grade 1) and resolved without dose modification or discontinuation. GSK3389404 administered subcutaneously was readily absorbed with a time to maximum plasma concentration (Tmax ) of 1-4 hours and an elimination half-life of 3-6 hours in plasma. Plasma area under the concentration-time curve (AUC) and maximum observed concentration (Cmax ) were dose-proportional. Dose-normalized plasma AUC from time 0 to infinity averaged 69.9 ng·h/(mL·mg dose) across cohorts, and Cmax 9.5 ng/(mL·mg dose). Pharmacokinetic profiles and parameters were comparable between single and multiple dosing. No accumulation was observed with once-weekly dosing. The metabolite was undetectable in urine and plasma. In the pooled urine, GSK3389404 was estimated to account for <0.1% of the total dose. In summary, GSK3389404 dosing has been tested up to 120 mg for 4 weeks with an acceptable safety and pharmacokinetic profile, supporting further clinical investigation in patients with chronic hepatitis B.

© 2019 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.
KEYWORDS:

GSK3389404; chronic hepatitis B; first-time-in-human; hepatitis B virus; pharmacokinetics

PMID:
    30861337
DOI:
    10.1002/cpdd.670

StephenW

Clin Pharmacol Drug Dev。 2019年3月12日doi：10.1002 / cpdd.670。 [印刷前的电子版]
一项随机，双盲，安慰剂对照，首次人体研究，用于评估GSK3389404在健康受试者中单次和多次上升剂量的安全性，耐受性和药代动力学。
Han K1，Cremer J2，Elston R3，Oliver S4，Baptiste-Brown S1，Chen S1，Gardiner D1，Davies M5，Saunders J1，Hamatake R2，Losos J2，Leivers M2，Hood S3，van der Berg F6，Paff M7，Ritter JM8，西奥多D2。
作者信息
抽象

GSK3389404是一种肝靶向反义寡核苷酸，可抑制乙型肝炎表面抗原和所有其他乙型肝炎病毒蛋白的合成。这项首次在人，随机，双盲，第1阶段的研究评估了皮下（SC）在健康受试者中施用的GSK3389404的安全性和药代动力学。四个单次递增剂量组（10mg，30mg，60mg和120mg）和3个多次递增剂量组（30mg，60mg和120mg，每周一次，共4周）各自包括随机分配至GSK3389404的6名受试者和2名受试者随机分配到安慰剂组。由于AE，没有严重的不良事件（AE）或退出。重复给药时安全性没有恶化。最常见的治疗相关AE是注射部位反应（19.0％[n = 8/42]，频率与剂量水平无关）;均为轻度（1级），无需剂量调整或停药即可解决。皮下给药的GSK3389404容易被吸收，最大血浆浓度（Tmax）为1-4小时，血浆中的消除半衰期为3-6小时。浓度 - 时间曲线下的血浆面积（AUC）和最大观察浓度（Cmax）是剂量成比例的。从时间0到无穷大的剂量标准化血浆AUC在组群中平均为69.9ng·h /（mL·mg剂量），并且Cmax为9.5ng /（mL·mg剂量）。单剂量和多剂量之间的药代动力学曲线和参数是相当的。每周一次给药未观察到累积。尿液和血浆中检测不到代谢物。在合并的尿液中，估计GSK3389404占总剂量的<0.1％。总之，GSK3389404剂量已经测试高达120毫克，持续4周，具有可接受的安全性和药代动力学特征，支持慢性乙型肝炎患者的进一步临床研究。

©2019作者。药物开发中的临床药理学由Wiley Periodicals，Inc。代表美国临床药理学院出版。
关键词：

GSK3389404;慢性乙型肝炎;第一 - 时间 - 在人类;乙型肝炎病毒;药代动力学

结论：
    30861337
DOI：
    10.1002 / cpdd.670

StephenW

https://accp1.onlinelibrary.wiley.com/doi/pdf/10.1002/cpdd.670