Safety Assessment UK, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, UK.
Br J Pharmacol. 2010 Jan;159(1):12-21. doi: 10.1111/j.1476-5381.2009.00207.x.
Owing to its association with Torsades de Pointes, drug-induced QT interval prolongation has been and remains a significant hurdle to the development of safe, effective medicines. Genetic and pharmacological evidence highlighting the pivotal role the human ether-a-go-go-related gene (hERG) channel was a critical step in understanding how to start addressing this issue. It led to the development of hERG assays with the rapid throughput needed for the short timescales required in early drug discovery. The resulting volume of hERG data has fostered in silico models to help chemists design compounds with reduced hERG potency. In early drug discovery, a pragmatic approach based on exceeding a given potency value has been required to decide when a compound is likely to carry a low QT risk, to support its progression to late-stage discovery. At this point, the in vivo efficacy and metabolism characteristics of the potential drug are generally defined, as well its safety profile, which includes usually a dog study to assess QT interval prolongation risk. The hERG and in vivo QT data, combined with the likely indication and the estimated free drug level for efficacy, are put together to assess the risk that the potential drug will prolong QT in man. Further data may be required to refine the risk assessment before making the major investment decisions for full development. The non-clinical data are essential to inform decisions about compound progression and to optimize the design of clinical QT studies.
由于与尖端扭转型室性心动过速有关，药物引起的 QT 间期延长一直是安全、有效药物开发的重大障碍。遗传和药理学证据强调了人类 ether-a-go-go 相关基因 (hERG) 通道的关键作用，这是理解如何解决这一问题的关键一步。它导致了 hERG 测定法的发展，具有早期药物发现所需的短时间尺度所需的快速通量。由此产生的大量 hERG 数据促进了计算模型的发展，以帮助化学家设计降低 hERG 效力的化合物。在早期药物发现中，基于超过给定效力值的务实方法被要求决定化合物何时可能具有低 QT 风险，以支持其进入后期发现阶段。此时，潜在药物的体内功效和代谢特征通常已被定义，其安全性概况也包括通常进行狗研究以评估 QT 间期延长风险。hERG 和体内 QT 数据，结合潜在的适应症和估计的功效游离药物水平，用于评估潜在药物是否会导致 QT 间期延长的风险。在做出全面开发的重大投资决策之前，可能需要进一步的数据来完善风险评估。非临床数据对于告知化合物进展决策和优化临床 QT 研究设计至关重要。
