de Jong Jan, Hellemans Peter, Jiao James Juhui, Huang Yuhan, Mesens Sofie, Sukbuntherng Juthamas, Ouellet Daniele
Janssen Research & Development, LLC, San Diego, CA, USA.
Pharmacyclics LLC, an AbbVie Company, Sunnyvale, USA.
Cancer Chemother Pharmacol. 2017 Dec;80(6):1227-1237. doi: 10.1007/s00280-017-3471-x. Epub 2017 Oct 28.
Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects.
Part 1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680 mg in eight subjects. Part 2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680 mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted.
No clinically relevant safety observations were noted in Part 1. During Part 2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680 mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were < 10 ms at all timepoints and at supratherapeutic C . Moxifloxacin showed the anticipated QTc effect, confirming assay sensitivity despite the early study termination. Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful.
Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval. CLINICALTRIALS.GOV: NCT02271438.
伊布替尼是一种口服的、不可逆的布鲁顿酪氨酸激酶抑制剂，用于治疗B细胞恶性肿瘤。本研究评估了单剂量伊布替尼在治疗和超治疗暴露水平下对健康受试者心脏复极化的影响。
第1部分采用开放标签、两阶段序贯设计，评估8名受试者单次服用840和1680mg伊布替尼的安全性和药代动力学。第2部分是一项随机、安慰剂和阳性（莫西沙星）对照、双盲、单剂量、四交叉研究，评估伊布替尼（840和1680mg）对QT/QTc间期的影响。计划招募64名健康受试者。使用线性混合效应模型将伊布替尼和莫西沙星（检测灵敏度）的基线校正QT（QTc）间期与安慰剂进行比较。还进行了浓度-QTc分析。
第1部分未观察到临床相关的安全性问题。在第2部分中，一名受试者在服用1680mg伊布替尼时出现4级ALT/AST升高，导致研究终止，入组人数限制为20名受试者。伊布替尼的暴露量呈剂量依赖性增加。在所有时间点和超治疗浓度下，伊布替尼与安慰剂之间QTc从基线变化的平均差异的90%CI上限均<10ms。莫西沙星显示出预期的QTc效应，尽管研究提前终止，但证实了检测灵敏度。伊布替尼导致QTc浓度依赖性轻度缩短和PR轻度延长，但这些影响不被认为具有临床意义。
伊布替尼的治疗浓度和超治疗浓度不会延长QTc间期。临床试验注册编号：NCT02271438。
