ERT, Rochester, New York, USA.
Eli Lilly & Company, Indiana, USA.
J Clin Pharmacol. 2020 Jan;60(1):125-139. doi: 10.1002/jcph.1502. Epub 2019 Aug 5.
The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late-stage electrocardiogram (ECG) monitoring for mildly QT-prolonging drugs. ECG waveforms from the IQ-CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT-prolonging drugs - moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine - and 1 negative drug, levocetirizine. A vector magnitude lead was derived from 12-lead ECGs, and measurements were made on a median beat from three 10-second replicates. Data were analyzed using a linear concentration-response model with QTcF and heart rate corrected JTpeak (JTpeak_c) as dependent variables. For moxifloxacin, dofetilide, and ondansetron, all pure hERG blockers, slopes of the concentration (C)-QTcF and C-JTpeak_c relationships were positive and statistically significant. With the prespecified linear model, the predicted effects on ΔΔQTcF and ΔΔJTpeak_c were 11.4 and 9.4 milliseconds for moxifloxacin at the geometric mean C on day 1, 9.0 and 11.7 milliseconds for dofetilide and 11.5, and 7.9 milliseconds for ondansetron, respectively. In contrast, dolasetron and quinine, both with additional ion channel effects, prolonged QTcF with a positive C-ΔQTcF slope and predicted ΔΔQTcF effect on day 1 of 6.2 and 11.4 milliseconds, whereas the C-ΔJTpeak_c slope and the predicted ΔΔJTpeak on day 1 were negative (-0.3 and -7.5 milliseconds per ng/mL). Pure hERG-blocking drugs prolonged both the QTc and the JTpeak_c intervals, whereas drugs with mixed ion channel effects, including peak sodium inhibition, prolonged QTcF but not the JTpeak_c interval.
JTpeak 间期已被提议作为一种新的生物标志物，以证明混合离子通道效应，从而可能减少轻度 QT 延长药物的晚期心电图（ECG）监测。使用 IQ-CSRC 研究的 ECG 波形。纳入了 20 名健康受试者，其中 6 名服用安慰剂，9 名分别服用 5 种轻度 QT 延长药物（莫西沙星、多非利特、昂丹司琼、多拉司琼和奎宁）和 1 种负性药物（左西替利嗪）。从 12 导联心电图中得出向量幅度导联，并在三个 10 秒重复的中位数搏动上进行测量。使用 QTcF 和心率校正的 JTpeak（JTpeak_c）作为因变量的线性浓度-反应模型分析数据。对于莫西沙星、多非利特和昂丹司琼，所有纯 hERG 阻滞剂，C-QTcF 和 C-JTpeak_c 关系的浓度（C）斜率均为正且具有统计学意义。根据预设的线性模型，莫西沙星在第 1 天的几何平均 C 时，对 ΔΔQTcF 和 ΔΔJTpeak_c 的预测效应分别为 11.4 和 9.4 毫秒，多非利特为 9.0 和 11.7 毫秒，昂丹司琼为 11.5 和 7.9 毫秒。相比之下，多拉司琼和奎宁均具有其他离子通道作用，其 QTcF 延长呈正 C-ΔQTcF 斜率，在第 1 天的预测 ΔΔQTcF 效应分别为 6.2 和 11.4 毫秒，而 C-ΔJTpeak_c 斜率和预测的第 1 天的 ΔΔJTpeak 为负（-0.3 和-7.5 毫秒/ng/mL）。纯 hERG 阻滞剂延长了 QTc 和 JTpeak_c 间期，而具有混合离子通道作用的药物，包括峰值钠抑制，延长了 QTcF 但没有延长 JTpeak_c 间期。
