Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA.
Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
Clin Pharmacol Ther. 2021 Jun;109(6):1606-1617. doi: 10.1002/cpt.2133. Epub 2020 Dec 29.
Drugs that prolong QT may cause torsade de pointes (TdP). However, translation of nonclinical assessment of QT prolongation or hERG channel, targeted by QT-prolonging drugs, into clinical TdP risk has been insufficient to date. In this blinded study, we confirmed the utility of a Normalized TdP Score System in predicting drug-induced TdP risks among 34 drugs, including 28 with low, intermediate, and high TdP risks under the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative plus six compounds with names blinded to the investigators, using the rabbit ventricular wedge assay. Concentration-dependent TdP scores were determined by drug-induced changes in QT, T , and proarrhythmias. Disclosure of the names and testing concentrations was made after completion of the experiments and report to the sponsors. Drugs' normalized TdP scores were calculated thereafter based on their respective free clinical maximum concentration (C ). Drugs' normalized TdP scores were calculated and ranked for 33 drugs, excluding 1 investigational drug, and the TdP risks of the 28 CiPA drugs were correctly distinguished according to their respective categories of low, intermediate, and high TdP risks under the CiPA initiative. Accordingly, we are able to propose the cutoff values of the normalized TdP scores at 1 × C : ≤ 0, > 0 to < 0.65 and ≥ 0.65, respectively, for low, intermediate, and high risk. This blinded study supports utility of our Normalized TdP Score System in predicting drug-induced TdP risks in 33 drugs, including 28 used for characterization of other assays under the CiPA initiative. However, these results need to be replicated in other laboratories.
延长 QT 的药物可能会导致尖端扭转型室性心动过速（TdP）。然而，迄今为止，将非临床评估 QT 延长或 hERG 通道（QT 延长药物的靶点）转化为临床 TdP 风险的工作还不够充分。在这项盲法研究中，我们使用兔心室楔形模型，通过 34 种药物（包括根据全面体外致心律失常试验（CiPA）计划被分类为低、中、高 TdP 风险的 28 种药物，以及另外 6 种名称被研究者屏蔽的化合物）证实了归一化 TdP 评分系统在预测药物诱导 TdP 风险方面的效用。通过药物引起的 QT、T 变化和致心律失常作用确定浓度依赖性 TdP 评分。在完成实验并向赞助商报告后，才披露药物名称和测试浓度。然后根据各自的游离临床最大浓度（C）计算药物的归一化 TdP 评分。对 33 种药物（排除 1 种研究药物）进行了归一化 TdP 评分的计算和排序，根据 CiPA 计划的低、中、高 TdP 风险分类，正确区分了 28 种 CiPA 药物的 TdP 风险。因此，我们能够提出归一化 TdP 评分的截断值为 1×C：≤0、>0 至 <0.65 和≥0.65，分别代表低、中、高风险。这项盲法研究支持我们的归一化 TdP 评分系统在预测 33 种药物（包括 28 种用于 CiPA 计划下其他检测方法特征描述的药物）诱导的 TdP 风险方面的效用。然而，这些结果需要在其他实验室中复制。
