Munasinghe Wijith, Stodtmann Sven, Tolcher Anthony, Calvo Emiliano, Gordon Michael, Jalving Mathilde, de Vos-Geelen Judith, Medina Diane, Bergau Dennis, Nuthalapati Silpa, Hoffman David, Shepherd Stacie, Xiong Hao
AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States.
AbbVie Deutschland GmbH & Co KG, Ludwigshafen am Rhein, Germany.
Cancer Chemother Pharmacol. 2016 Nov;78(5):1003-1011. doi: 10.1007/s00280-016-3156-x. Epub 2016 Oct 5.
Veliparib (ABT-888) is an orally bioavailable potent inhibitor of poly(ADP-ribose) polymerase (PARP)-1 and PARP-2. This phase 1 study evaluated the effect of veliparib on corrected QT interval using Fridericia's formula (QTcF).
Eligible patients with advanced solid tumors received single-dose oral veliparib (200 mg or 400 mg) or placebo in a 6-sequence, 3-period crossover design. The primary endpoint was the difference in the mean baseline-adjusted QTcF between 400 mg veliparib and placebo (∆∆QTcF) at six post-dose time points. Absence of clinically relevant QTcF effect was shown if the 95 % upper confidence bound (UCB) for the mean ∆∆QTcF was <10 ms for all time points. An exposure-response analysis was also performed.
Forty-seven patients were enrolled. Maximum mean ∆∆QTcF of veliparib 400 mg was 6.4 ms, with a 95 % UCB of 8.9 ms; for veliparib 200 mg, the maximum mean ∆∆QTcF was 3.6 ms, with a 95 % UCB of 6.1 ms. No patient had a QTcF value >480 ms or change from baseline in QTcF interval >30 ms. Treatment-emergent adverse events (TEAEs) were experienced by 36.2, 48.9, and 47.8 % of patients while receiving veliparib 200 mg, veliparib 400 mg, and placebo, respectively. Most common TEAEs were nausea (12.8 %) and myalgia (8.5 %) after veliparib 200 mg, nausea (8.5 %) and vomiting (8.5 %) after veliparib 400 mg, and nausea (6.5 %) after placebo.
Single-dose veliparib (200 mg or 400 mg) did not result in clinically significant QTc prolongation and was well tolerated in patients with advanced solid tumors.
维利帕尼（ABT - 888）是一种口服生物利用度高的聚（ADP - 核糖）聚合酶（PARP）-1和PARP - 2强效抑制剂。这项1期研究使用弗里德里西亚公式（QTcF）评估了维利帕尼对校正QT间期的影响。
符合条件的晚期实体瘤患者在6序列、3周期交叉设计中接受单剂量口服维利帕尼（200 mg或400 mg）或安慰剂。主要终点是在六个给药后时间点，400 mg维利帕尼与安慰剂之间的平均基线校正QTcF差异（∆∆QTcF）。如果所有时间点的平均∆∆QTcF的95%上置信区间（UCB）<10 ms，则表明不存在临床相关的QTcF效应。还进行了暴露-反应分析。
共纳入47例患者。400 mg维利帕尼的最大平均∆∆QTcF为6.4 ms，95% UCB为8.9 ms；200 mg维利帕尼的最大平均∆∆QTcF为3.6 ms，95% UCB为6.1 ms。没有患者的QTcF值>480 ms或QTcF间期相对于基线的变化>30 ms。接受200 mg维利帕尼、400 mg维利帕尼和安慰剂治疗的患者中，分别有36.2%、48.9%和47.8%经历了治疗中出现的不良事件（TEAE）。200 mg维利帕尼治疗后最常见的TEAE是恶心（12.8%）和肌痛（8.5%），400 mg维利帕尼治疗后是恶心（8.5%）和呕吐（8.5%），安慰剂治疗后是恶心（6.5%）。
单剂量维利帕尼（200 mg或400 mg）不会导致临床上显著的QTc延长，并且在晚期实体瘤患者中耐受性良好。
