An introduction to QT interval prolongation and non‐clinical approaches to assessing and reducing risk

Abstract

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. Redfern et al., 2003). Given the cost of bringing a new drug to the market [estimated in the year 2000 at approximately US$800m (DiMasi et al., 2003)], the proportion of drugs withdrawn owing to QT prolongation/TdP was a significant concern for pharmaceutical companies. The headline drugs withdrawn from sale were just the tip of the iceberg, however, as the development of many more potential drugs was halted following evidence of a QT prolongation risk and some drugs remain on sale despite carrying a QT risk but cannot be prescribed to certain patient groups. Such was the level of concern in the pharmaceutical industry that the 'QT issue' was jokingly dubbed 'Pharmageddon' (WS Redfern, pers. comm.). All in all this was, and remains, a significant hurdle to the development of effective but safe medicines in an industry needing to focus on improving its productivity by reducing safety-related attrition. This overview aims to introduce the topic and summarize non-clinical strategies to assess and reduce QT interval prolongation risk. It builds on a previous review of the topic and complements more specific case studies described by Valentin et al. (2010) and is considered from a broader perspective in the commentary by Guth and Rast (2010). British Journal of Pharmacology

A New Perspective in the Field of Cardiac Safety Testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm

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Disease Models for the Genetic Cardiac Diseases

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