siRNA JNJ-73763989 在健康中国成人参与者中的药代动力学、安全

StephenW

siRNA JNJ-73763989 在健康中国成人参与者中的药代动力学、安全性和耐受性
李海燕 1 2 、牛小叶 2 、张宇 3 、张丹宁 2 、张延庆 3 、王立群 4 、苗永庆 5 、姜延新 6 、季佳 4 、陈巧巧 5 、吴晓云 6 、Emmanuel Njumbe Ediage 7 、 Thomas N Kakuda 8 岁，Michael Biermer 7 岁
隶属关系
隶属关系

    1个
    中国北京，北京大学第三医院心血管内科和血管医学研究所。
    2个
    北京大学第三医院药物临床试验中心，北京，中国。
    3个
    天津市第五中心医院药物临床试验中心 I 期单位，天津，中国。
    4个
    临床药理学和药理学，杨森中国研发中心，北京，中国。
    5个
    临床开发，杨森中国研发中心，中国北京。
    6个
    杨森中国研发中心，中国上海。
    7
    Janssen Pharmaceutica NV，Beerse，比利时。
    8个
    Janssen Research & Development，美国加利福尼亚州南旧金山。

    PMID：36415122 DOI：10.1002/cpdd.1197

抽象的

JNJ-73763989 由 2 个短干扰 RNA 触发器 JNJ-73763976 和 JNJ-73763924 组成，靶向所有乙型肝炎病毒信使 RNA，从而减少所有病毒蛋白。在这项 1 期单中心、开放标签、平行组、随机研究中，参与者接受了 1 次 JNJ-73763989（100 或 200 mg）皮下注射，以研究 JNJ-73763989 在治疗中的药代动力学、安全性和耐受性健康的中国成年参与者。给药后最多 48 小时确定每个触发因素的血浆和尿液药代动力学参数。招募了 18 名参与者，每个剂量组 9 名。中位年龄和体重分别为 33.0 岁和 73.65 公斤； 83.3%为男性。两种触发器的暴露按比例增加剂量。达到最大浓度的中位时间范围为 6.0 至 10.0 小时，平均消除半衰期范围为 4.5 至 4.8 小时，包括触发因素和剂量。对于 100 和 200 毫克剂量组，JNJ-73763976 和 JNJ-73763924 的平均尿排泄率分别为 17.7% 至 19.4% 和 13.1% 至 13.2%。所有治疗中出现的不良事件 (AE) 都是轻微的，并在研究结束时得到解决，没有 AE 或严重的 AE 导致研究过早中止或死亡。总体而言，JNJ-73763989在健康中国参与者中的药代动力学与之前的研究一致，JNJ-73763989在单次给药后总体安全且耐受性良好。

关键词：中文； JNJ-3989； JNJ-73763989；乙型肝炎；药代动力学；干扰核糖核酸；病毒性肝炎。

© 2022，美国临床药理学会。

StephenW

Pharmacokinetics, Safety, and Tolerability of the siRNA JNJ-73763989 in Healthy Chinese Adult Participants
Haiyan Li  1   2 , Xiaoye Niu  2 , Yu Zhang  3 , Danning Zhang  2 , Yanqing Zhang  3 , Liqun Wang  4 , Yongqing Miao  5 , Yanxin Jiang  6 , Jia Ji  4 , Qiaoqiao Chen  5 , Xiaoyun Wu  6 , Emmanuel Njumbe Ediage  7 , Thomas N Kakuda  8 , Michael Biermer  7
Affiliations
Affiliations

    1
    Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
    2
    Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.
    3
    Phase I Unit of Drug Clinical Trial Center, Tianjin Fifth Central Hospital, Tianjin, China.
    4
    Clinical Pharmacology and Pharmacometrics, Janssen China Research & Development, Beijing, China.
    5
    Clinical Development, Janssen China Research & Development, Beijing, China.
    6
    Janssen China Research & Development, Shanghai, China.
    7
    Janssen Pharmaceutica NV, Beerse, Belgium.
    8
    Janssen Research & Development, South San Francisco, California, USA.

    PMID: 36415122 DOI: 10.1002/cpdd.1197

Abstract

JNJ-73763989, composed of the 2 short-interfering RNA triggers JNJ-73763976 and JNJ-73763924, targets all hepatitis B virus messenger RNAs, thereby reducing all viral proteins. In this phase 1, single-site, open-label, parallel-group, randomized study, participants were given 1 subcutaneous injection of JNJ-73763989 (100 or 200 mg) to investigate the pharmacokinetics, safety, and tolerability of JNJ-73763989 in healthy Chinese adult participants. Plasma and urine pharmacokinetic parameters were determined for each trigger up to 48 hours after dosing. Eighteen participants, 9 per dose group, were enrolled. The median age and weight were 33.0 years and 73.65 kg; 83.3% were male. Exposure of both triggers increased dose proportionally. Median time to maximum concentration ranged from 6.0 to 10.0 hours, and mean elimination half-life ranged from 4.5 to 4.8 hours across both triggers and doses. Mean urinary excretion for JNJ-73763976 and JNJ-73763924 ranged from 17.7% to 19.4% and 13.1% to 13.2% for the 100- and 200-mg dose groups, respectively. All treatment-emergent adverse events (AEs) were mild and resolved by study end, and no AEs or serious AEs resulted in premature study discontinuation or death. Overall, the pharmacokinetics of JNJ-73763989 in healthy Chinese participants were consistent with previous studies, and JNJ-73763989 was generally safe and well tolerated after a single dose.

Keywords: Chinese; JNJ-3989; JNJ-73763989; hepatitis B; pharmacokinetics; siRNA; viral hepatitis.

© 2022, The American College of Clinical Pharmacology.