Gotta Verena, Yu Zhiyi, Cools Frank, van Ammel Karel, Gallacher David J, Visser Sandra A G, Sannajust Frederick, Morissette Pierre, Danhof Meindert, van der Graaf Piet H
Systems Pharmacology Leiden Academic Centre for Drug Research (LACDR) Leiden University Leiden The Netherlands; Pediatric Pharmacology and Pharmacometrics University of Basel Children's Hospital (UKBB) Basel Switzerland.
Division of Medicinal Chemistry Leiden Academic Centre for Drug Research (LACDR) Leiden University Leiden The Netherlands.
Pharmacol Res Perspect. 2016 Nov 17;4(6):e00270. doi: 10.1002/prp2.270. eCollection 2016 Dec.
Drug-induced QTc interval prolongation ( QTc) is a main surrogate for proarrhythmic risk assessment. A higher in vivo than in vitro potency for hERG-mediated QTc prolongation has been suggested. Also, in vivo between-species and patient populations' sensitivity to drug-induced QTc prolongation seems to differ. Here, a systems pharmacology model integrating preclinical in vitro (hERG binding) and in vivo (conscious dog QTc) data of three hERG blockers (dofetilide, sotalol, moxifloxacin) was applied (1) to compare the operational efficacy of the three drugs in vivo and (2) to quantify dog-human differences in sensitivity to drug-induced QTc prolongation (for dofetilide only). Scaling parameters for translational in vivo extrapolation of drug effects were derived based on the assumption of system-specific myocardial ion channel densities and transduction of ion channel block: the operational efficacy (transduction of hERG block) in dogs was drug specific (1-19% hERG block corresponded to ≥10 msec QTc). System-specific maximal achievable QTc was estimated to 28% from baseline in both dog and human, while %hERG block leading to half-maximal effects was 58% lower in human, suggesting a higher contribution of hERG-mediated potassium current to cardiac repolarization. These results suggest that differences in sensitivity to drug-induced QTc prolongation may be well explained by drug- and system-specific differences in operational efficacy (transduction of hERG block), consistent with experimental reports. The proposed scaling approach may thus assist the translational risk assessment of QTc prolongation in different species and patient populations, if mediated by the hERG channel.
药物诱导的QTc间期延长（QTc）是心律失常风险评估的主要替代指标。有研究表明，hERG介导的QTc延长在体内的效力高于体外。此外，体内不同物种和患者群体对药物诱导的QTc延长的敏感性似乎存在差异。在此，应用了一个系统药理学模型，该模型整合了三种hERG阻滞剂（多非利特、索他洛尔、莫西沙星）的临床前体外（hERG结合）和体内（清醒犬QTc）数据，用于（1）比较这三种药物在体内的作用效果，以及（2）量化犬与人对药物诱导的QTc延长的敏感性差异（仅针对多非利特）。基于特定系统的心肌离子通道密度和离子通道阻滞转导的假设，得出了药物效应体内外转化的缩放参数：犬体内的作用效果（hERG阻滞的转导）具有药物特异性（1 - 19%的hERG阻滞对应≥10毫秒的QTc）。估计犬和人的特定系统最大可实现QTc较基线分别增加28%，而导致半数最大效应的hERG阻滞百分比在人中低58%，这表明hERG介导的钾电流对心脏复极化的贡献更大。这些结果表明，对药物诱导的QTc延长的敏感性差异可能很好地由药物和特定系统在作用效果（hERG阻滞的转导）方面的差异来解释，这与实验报告一致。因此，如果由hERG通道介导，所提出的缩放方法可能有助于不同物种和患者群体中QTc延长的转化风险评估。
