Drug Disposition, Toxicology and PKPD, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Drug Disposition, Toxicology and PKPD, Eli Lilly and Company, Indianapolis, IN 46285, USA.
J Pharmacol Toxicol Methods. 2020 Sep;105:106900. doi: 10.1016/j.vascn.2020.106900. Epub 2020 Aug 5.
It has been two decades since screening new molecules and potential clinical drug candidates against the hERG potassium channel became a routine part of safety pharmacology. The earliest heuristic for what was an adequate safety margin to separate molecules with a potential liability to cause the arrhythmia torsade de pointes (TdP) from those with no such liability emerged in 2002 and was determined to be a hERG IC value 30-fold above the therapeutic free plasma concentration (Webster, Leishman, & Walker, 2002). In the intervening years nonclinical and clinical ICH guidance has been introduced and intense scrutiny has been applied to the QT interval of the electrocardiogram in animals and man. Has the 30-fold heuristic stood the test of time?
The hERG margins between the IC value and the therapeutic unbound plasma concentrations were examined for 367 compounds. These margins were compared against the categories used by www.CredibleMeds.com to classify a drug's TdP risk. A subset of 336 of these drugs were compared against their US product labels with respect to black box warnings on QTc prolongation or TdP, warnings and precautions on QTc or TdP, and QTc language in the clinical pharmacology section.
Against the CredibleMeds classification the means of the margins for Known, Conditional, or Possible Risk of TdP, and Not Listed (presumably no TdP liability) were 4.8, 28, 71 and 339, respectively. Against the US label language the means of margins for black boxes and warnings were 3.1 and 26, respectively. The average margins associated with, positive QTc outcome, negative QTc outcome and no QTc language were 16, 479 and 204, respectively. Based on ROC curves the optimal hERG margin thresholds to separate "Known risk of TdP" from "Not Listed" and, QTc prolongation positive from QTc negative were 37- and 50-fold, respectively.
The observed optimal margin of 50-fold in the current study is not appreciably different from a previously reported 45-fold optimal margin (Gintant, 2011). The margin falls between the margins for negative (QTc outcome or no QTc language) and positive (positive QTc outcome, warnings or black boxes) compounds. The observed optimal margin of 37-fold in the current study is not appreciably different from the commonly used 30-fold optimal margin (Webster et al., 2002). This margin falls between those for drugs with a known or conditional TdP risk and those where it is at best a possible risk, and from the 240 drugs not listed on www.CredibleMeds.com. It is expected that there would be a small numerical difference (e.g. 37 vs. 50, or as previously published 30 vs. 45) between optimal cut-offs for the TdP liability and QTc prolongation predictions since some QTc positive drugs are described on CredibleMeds.com as having only a "Possible Risk of TdP" as they are not associated with TdP when used as directed. The fact that the margins in each category form distributions is also expected given biologic variability. However, we argue that a more consistent manner of assessing hERG potency and evaluating relevant exposures would be likely to reduce the spread in these distributions and make margins even more useful as a decision-making data point.
自 2002 年以来，筛选针对 hERG 钾通道的新分子和潜在临床候选药物已成为安全药理学的常规部分，距今已有二十年。当时出现了一个早期的启发式方法，用于确定具有致心律失常尖端扭转型室性心动过速（TdP）潜在风险的分子与没有此类风险的分子之间的适当安全裕度，即 hERG 的 IC 值比治疗游离血浆浓度高出 30 倍（Webster、Leishman 和 Walker，2002）。在这期间，非临床和临床 ICH 指南已经出台，对动物和人体内心电图的 QT 间期进行了严格审查。30 倍的启发式方法是否经受住了时间的考验？
对 367 种化合物的 hERG 界限（IC 值与治疗未结合血浆浓度之间的界限）进行了检查。这些边界与 www.CredibleMeds.com 用于分类药物 TdP 风险的类别进行了比较。对其中 336 种药物的亚组，根据美国产品标签，对 QTc 延长或 TdP 的黑框警告、关于 QTc 或 TdP 的警告和注意事项以及临床药理学部分的 QTc 语言进行了比较。
根据 CredibleMeds 分类，已知、有条件或可能存在 TdP 风险和未列入（推测没有 TdP 责任）的药物的平均边界分别为 4.8、28、71 和 339。根据美国标签语言，黑框和警告的平均边界分别为 3.1 和 26。与阳性 QTc 结果、阴性 QTc 结果和无 QTc 语言相关的平均边界分别为 16、479 和 204。基于 ROC 曲线，将“已知 TdP 风险”与“未列入”和 QTc 延长阳性与 QTc 阴性分开的最佳 hERG 边界阈值分别为 37 倍和 50 倍。
本研究中观察到的最佳边界 50 倍与之前报道的最佳边界 45 倍（Gintant，2011）没有明显差异。该边界介于 QTc 延长阳性和 QTc 阴性化合物之间。本研究中观察到的最佳边界 37 倍与常用的 30 倍最佳边界（Webster 等人，2002）没有明显差异。该边界介于具有已知或有条件 TdP 风险的药物和那些最好是可能风险的药物之间，以及在 www.CredibleMeds.com 上未列出的 240 种药物之间。预计 TdP 责任和 QTc 延长预测的最佳截止值之间会存在较小的数值差异（例如 37 倍与 50 倍，或之前发表的 30 倍与 45 倍），因为一些 QTc 阳性药物在 CredibleMeds.com 上被描述为仅具有“可能的 TdP 风险”，因为它们在按规定使用时不会导致 TdP。由于存在生物学变异性，因此在每个类别中形成分布的边界也是可以预期的。然而，我们认为，更一致地评估 hERG 效力和评估相关暴露量可能会减少这些分布的分散性，并使边界更有用，成为决策数据点。
