Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Janssen Research & Development, 1400 McKean Road, Spring House, PA, 19477, USA.
Cancer Chemother Pharmacol. 2018 Sep;82(3):457-468. doi: 10.1007/s00280-018-3632-6. Epub 2018 Jul 5.
Phase Ib study evaluating the effect of apalutamide, at therapeutic exposure, on ventricular repolarization by applying time-matched pharmacokinetics and electrocardiography (ECG) in patients with castration-resistant prostate cancer. Safety of daily apalutamide was also assessed.
Patients received 240 mg oral apalutamide daily. Time-matched ECGs were collected via continuous 12-lead Holter recording before apalutamide (Day - 1) and on Days 1 and 57 (Cycle 3 Day 1). Pharmacokinetics of apalutamide were assessed on Days 1 and 57 at matched time points of ECG collection. QT interval was corrected for heart rate using Fridericia correction (QTcF). The primary endpoint was the maximum mean change in QTcF (ΔQTcF) from baseline to Cycle 3 Day 1 (steady state). Secondary endpoints were the effect of apalutamide on other ECG parameters, pharmacokinetics of apalutamide and its active metabolite, relationship between plasma concentrations of apalutamide and QTcF, and safety.
Forty-five men were enrolled; 82% received treatment for ≥ 3 months. At steady state, the maximum ΔQTcF was 12.4 ms and the upper bound of its associated 90% CI was 16.0 ms. No clinically meaningful effects of apalutamide were reported for heart rate or other ECG parameters. A concentration-dependent increase in QTcF was observed for apalutamide. Most adverse events (AEs) (73%) were grade 1-2 in severity. No patients discontinued due to QTc prolongation or AEs.
The effect of apalutamide on QTc prolongation was modest and does not produce a clinically meaningful effect on ventricular repolarization. The AE profile was consistent with other studies of apalutamide.
评估在去势抵抗性前列腺癌患者中，以治疗暴露水平给予阿帕鲁胺对心室复极的影响，方法为应用时间匹配的药代动力学和心电图（ECG）。还评估了每日阿帕鲁胺的安全性。
患者接受 240 mg 口服阿帕鲁胺每日一次。在阿帕鲁胺（第-1 天）之前和第 1 天和第 57 天（第 3 周期第 1 天）通过连续 12 导联 Holter 记录收集时间匹配的 ECG。在第 1 天和第 57 天，在 ECG 采集的匹配时间点评估阿帕鲁胺的药代动力学。使用 Fridericia 校正（QTcF）校正心率后的 QT 间期。主要终点是从基线到第 3 周期第 1 天（稳态）的 QTcF 最大平均变化（ΔQTcF）。次要终点是阿帕鲁胺对其他 ECG 参数的影响、阿帕鲁胺及其活性代谢物的药代动力学、阿帕鲁胺血浆浓度与 QTcF 的关系以及安全性。
共纳入 45 名男性；82%的患者接受治疗≥3 个月。在稳态时，最大 ΔQTcF 为 12.4 ms，其 90%置信区间的上限为 16.0 ms。阿帕鲁胺对心率或其他 ECG 参数无临床意义的影响。观察到阿帕鲁胺的 QTcF 呈浓度依赖性增加。大多数不良事件（AE）（73%）的严重程度为 1-2 级。没有患者因 QTc 延长或 AE 而停药。
阿帕鲁胺对 QTc 延长的影响适度，不会对心室复极产生临床意义的影响。AE 谱与其他阿帕鲁胺研究一致。
