Clinical Pharmacology, AbbVie, North Chicago, IL, USA.
Immunology Development, AbbVie, North Chicago, IL, USA.
Clin Ther. 2024 Oct;46(10):733-741. doi: 10.1016/j.clinthera.2024.07.003. Epub 2024 Aug 13.
This study aims to characterize the pharmacokinetics, safety, tolerability, and exploratory efficacy of upadacitinib, an oral Janus kinase inhibitor approved for treating moderate to severe atopic dermatitis (AD) in adults and adolescents, in children with severe AD.
In an open-label, multiple-dose, Phase 1 study, pediatric patients with severe AD from two age groups (2 to <6 years and 6 to <12 years) received bodyweight-based dosing regimens of upadacitinib using either twice-daily immediate-release (IR) oral solution or once-daily extended-release (ER) tablets. A pharmacokinetic assessment was conducted on Day 7 of the study, which was followed by a long-term safety and exploratory efficacy evaluation for up to 108 weeks. The results reported here are based on an interim analysis when the study had completed enrollment and pharmacokinetic assessment.
A total of 35 patients were enrolled and received upadacitinib. The maximum upadacitinib plasma concentration was attained within a median time of 0.5 to 2 hours and 2 to 2.5 hours for the IR oral solution and ER tablet formulations, respectively. Upadacitinib functional half-life was generally shorter with IR oral solution relative to ER tablets. Upadacitinib apparent oral clearance decreased with decreasing body weight in the pediatric patients enrolled in this study. Upadacitinib was generally safe and well tolerated. The most common (≥3 patients) adverse events were upper respiratory tract infection, COVID-19 infection, headache, abdominal discomfort, vomiting, asthma, and cough. No new safety risks were identified compared to the known safety profile for upadacitinib in adults and adolescents. In the 30 patients with available exploratory efficacy data at Week 12, 36.7% achieved validated Investigator's Global Assessment scale for AD score of 0 or 1 (Validated Investigator Global Assessment for AD 0/1), and 70.0% had Eczema Area and Severity Index (EASI) improvement of at least 75% (EASI 75).
The characterized pharmacokinetic profiles in this study, together with the observed safety and exploratory efficacy results, support further investigation of the current upadacitinib dosing regimen in future confirmatory Phase 3 clinical trials in children with AD.
NCT03646604, registered 2018-08-23.
本研究旨在描述已获批用于治疗成人和青少年中重度特应性皮炎（AD）的口服 JAK 抑制剂 upadacitinib 在重度 AD 儿童患者中的药代动力学、安全性、耐受性和探索性疗效。
在一项开放标签、多剂量、1 期研究中，来自两个年龄组（2 岁至<6 岁和 6 岁至<12 岁）的重度 AD 儿科患者按照体重接受了 upadacitinib 的剂量方案，使用每日两次的即时释放（IR）口服溶液或每日一次的延长释放（ER）片剂。在研究的第 7 天进行了药代动力学评估，随后进行了长达 108 周的长期安全性和探索性疗效评估。此处报告的结果基于研究完成入组和药代动力学评估时的中期分析。
共有 35 名患者入组并接受了 upadacitinib 治疗。IR 口服溶液和 ER 片剂的最大 upadacitinib 血浆浓度达到中位时间分别为 0.5 至 2 小时和 2 至 2.5 小时。与 ER 片剂相比，IR 口服溶液中 upadacitinib 的功能半衰期通常较短。在本研究中纳入的儿科患者中，随着体重的降低，upadacitinib 的表观口服清除率降低。upadacitinib 通常是安全且耐受良好的。最常见（≥3 例）的不良事件是上呼吸道感染、COVID-19 感染、头痛、腹部不适、呕吐、哮喘和咳嗽。与成人和青少年中已知的 upadacitinib 安全性概况相比，没有发现新的安全性风险。在 30 名可获得第 12 周探索性疗效数据的患者中，36.7%达到了 AD 评分 0 或 1（验证的研究者全球评估 AD 评分 0/1）的有效标准，70.0%的患者 EASI（Eczema Area and Severity Index）改善至少 75%（EASI 75）。
本研究中描述的药代动力学特征，以及观察到的安全性和探索性疗效结果，支持在未来的 AD 儿童患者中进行确证性 3 期临床试验中进一步研究当前的 upadacitinib 剂量方案。
NCT03646604，注册于 2018 年 8 月 23 日。
