Astellas Pharma Inc, Tokyo, Japan.
Astellas Pharma Inc, Tokyo, Japan.
Clin Ther. 2020 Aug;42(8):1483-1493.e1. doi: 10.1016/j.clinthera.2020.06.002. Epub 2020 Aug 11.
Quetiapine has been reported to prolong the QT interval, and has been used as a positive control in thorough QT studies. The objective of the present study was to evaluate, in the late stages of clinical development, the QT-prolongation effects of the extended-release (XR) formulation of quetiapine at the approved dose in Japanese patients with bipolar disorder, using concentration-QT modeling and simulation.
Plasma concentrations of quetiapine and 4 of its metabolites (M1, M2, M4, and M5), and the QT interval corrected using the Fridericia formula (QTcF), were used for the concentration-QT analysis. Data from intensive electrocardiogram monitoring at predose and at 4, 6, 10, and 24 h after the administration of the last dose were pooled from a Phase I trial (6949-CL-0006) and from sparse sampling in late-stage clinical trials (6949-CL-0005, -0021, -0022, and -0023) in Japanese patients (N = 505). The upper limit of 1-sided 95% confidence interval (CI) of the changes from baseline in QTcF (ΔQTcF) at the geometric mean Cmax of a therapeutic dose of 300 mg once daily was predicted using a linear mixed-effects model, with the intercept as a random effect specifying a subject effect.
For quetiapine and M2, but not M1, M4, or M5, positive slopes were observed between ΔQTcF and concentration. The predicted upper limits of the 1-sided 95% CIs did not exceed the regulatory threshold of 10 msec. Therefore, QTc prolongation is unlikely to be clinically relevant at the approved dose of quetiapine XR.
In this pooled data analysis of the QT-prolongation effects of the quetiapine XR, positive relationships between ΔQTcF and quetiapine and M2 concentrations were observed. However, the predicted upper limits of the 1-sided 95% CIs did not exceed 10 msec. Therefore, QTc prolongation is unlikely to be clinically relevant at the approved dose. ClinicalTrials.gov identifiers: NCT01725282, NCT01919008, NCT01725308, NCT01737268, and NCT02362412.
喹硫平已被报道可延长 QT 间期，并已被用作全面 QT 研究的阳性对照。本研究的目的是在日本双相情感障碍患者的临床开发后期阶段，使用浓度-QT 建模和模拟评估批准剂量的喹硫平延长释放（XR）制剂的 QT 延长作用。
使用喹硫平和其 4 种代谢物（M1、M2、M4 和 M5）的血浆浓度以及使用 Fridericia 公式校正的 QT 间期（QTcF）进行浓度-QT 分析。从一项 I 期试验（6949-CL-0006）和晚期临床试验的稀疏采样中（6949-CL-0005、-0021、-0022 和 -0023）汇总了在最后一次给药后 4、6、10 和 24 小时时的空腹和给药前的心电图监测数据，以评估日本患者（N=505）接受每日一次 300mg 治疗剂量的喹硫平的 QTcF（ΔQTcF）自基线的变化的上限（1 侧 95%置信区间[CI]）使用线性混合效应模型进行预测，截距为随机效应，指定个体效应。
对于喹硫平和 M2，但不是 M1、M4 或 M5，观察到 ΔQTcF 与浓度之间存在正斜率。预测的 1 侧 95%CI 的上限未超过 10 msec 的监管阈值。因此，在批准的喹硫平 XR 剂量下，QTc 延长不太可能具有临床相关性。
在对喹硫平 XR 的 QT 延长作用的汇总数据分析中，观察到 ΔQTcF 与喹硫平和 M2 浓度之间存在正相关关系。然而，预测的 1 侧 95%CI 的上限未超过 10 msec。因此，在批准剂量下，QTc 延长不太可能具有临床相关性。临床试验.gov 标识符：NCT01725282、NCT01919008、NCT01725308、NCT01737268 和 NCT02362412。
