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Abstract：
Parsaclisib, a potent and selective phosphatidylinositol 3 kinase δ inhibitor, has been investigated for the treatment of B-cell malignancies and studied in patients with autoimmune diseases and myelofibrosis. The CITADEL-101 study (NCT02018861) assessed safety, tolerability, and preliminary efficacy of parsaclisib in patients with relapsed or refractory non-Hodgkin lymphoma. This study evaluated the cardiac safety of parsaclisib as monotherapy based on data from 72 patients enrolled in the CITADEL-101 study. Time-matched pharmacokinetic and ECG measurements were collected at specified times for 69 patients receiving monotherapy in doses of 5, 10, 15, 20, 30, and 45 mg once daily. Based on the categorical outlier analysis, no dose-dependent effect was observed on the incidence of outliers in QT interval corrected for heart rate (HR) by Fridericia\'s method (QTcF), HR, or cardiac conduction. Based on central tendency analysis, the least square means (LSMs) (90% confidence interval [CI]) of ΔQTcF from the central tendency analysis ranged from -6.83 (-18.8 to 5.19) to 4.75 ms (0.410-9.09) across dose groups (below 20 ms, the threshold of large QT effects) and was not considered dose dependent. Moreover, the LSMs of ΔHR, ΔPR interval, and ΔQRS interval were minor. From the concentration-ΔQTcF analyses, the predicted ΔQTcF (90% CI) for all dose levels was between 0.365 (-1.75 to 2.48) and 7.87 ms (0.921-14.8), with the highest upper limit of CIs well below 20 ms, and therefore, a large QT/QTc effect was ruled out up to the highest dose level (45 mg) investigated. Overall, parsaclisib at the dose ranges studied did not reveal concentration-dependent effects on change in QTcF and did not have a significant effect on HR or cardiac conduction.
摘要：
Parsaclisib,一种有效和选择性的磷脂酰肌醇3激酶δ抑制剂，已对B细胞恶性肿瘤的治疗进行了研究，并在患有自身免疫性疾病和骨髓纤维化的患者中进行了研究。CITADEL-101研究（NCT02018861）评估了安全性，耐受性,和parsaclisib对复发或难治性非霍奇金淋巴瘤患者的初步疗效。这项研究基于来自CITADEL-101研究中的72名患者的数据，评估了parsaclib作为单一疗法的心脏安全性。在指定时间收集69例患者的时间匹配的药代动力学和ECG测量值，这些患者每天一次接受5、10、15、20、30和45mg剂量的单一疗法。基于分类离群值分析，通过Fridericia方法（QTcF）对心率（HR）校正的QT间期异常值的发生率没有观察到剂量依赖性影响，HR,或者心脏传导.基于中心趋势分析，中心趋势分析的ΔQTcF的最小二乘均值（LSM）（90％置信区间[CI]）在剂量组之间（低于20ms，范围为-6.83（-18.8至5.19）至4.75ms（0.410-9.09），大QT效应的阈值），并且不被认为是剂量依赖性的。此外，ΔHR的LSM，ΔPR间隔，ΔQRS间期较小。从浓度-ΔQTcF分析，所有剂量水平的预测ΔQTcF（90％CI）在0.365（-1.75至2.48）和7.87ms（0.921-14.8）之间，CI的最高上限远低于20毫秒，因此,在所研究的最高剂量水平（45mg）下，排除了较大的QT/QTc效应。总的来说,在所研究的剂量范围内,parsaclisib未发现对QTcF变化的浓度依赖性影响,对HR或心脏传导没有显著影响.
