Strategies to reduce the risk of drug-induced QT interval prolongation: a pharmaceutical company perspective

Abstract

Drug-induced prolongation of the QT interval is having a significant impact on the ability of the pharmaceutical industry to develop new drugs. The development implications for a compound causing a significant effect in the 'Thorough QT/QTc Study' -- as defined in the clinical regulatory guidance (ICH E14) -- are substantial. In view of this, and the fact that QT interval prolongation is linked to direct inhibition of the hERG channel, in the early stages of drug discovery the focus is on testing for and screening out hERG activity. This has led to understanding of how to produce low potency hERG blockers whilst retaining desirable properties. Despite this, a number of factors mean that when an integrated risk assessment is generated towards the end of the discovery phase (by conducting at least an in vivo QT assessment) a QT interval prolongation risk is still often apparent; inhibition of hERG channel trafficking and partitioning into cardiac tissue are just two confounding factors. However, emerging information suggests that hERG safety margins have high predictive value and that when hERG and in vivo non-clinical data are combined, their predictive value to man, whilst not perfect, is >80%. Although understanding the anomalies is important and is being addressed, of greater importance is developing a better understanding of TdP, with the aim of being able to predict TdP rather than using an imperfect surrogate marker (QT interval prolongation). Without an understanding of how to predict TdP risk, high-benefit drugs for serious indications may never be marketed.

Figure 1

A generic, non-clinical strategy to reduce QT interval prolongation risk in man. Following compound design and synthesis, testing in a human ether-a-go-go-related gene (hERG) assay is the first step. A critical factor is feeding back potency data to medicinal chemists in a time frame short enough to influence compound design, hence, the need for a hERG assay with good throughput. The structure of each compound tested and its hERG potency data are ideally also used to feed in silico models of hERG activity to aid the compound design step. Compounds are categorized as candidates for further evaluation if their hERG potency exceeds predefined criteria. If the hERG profile and other attributes of a compound make it a potential candidate drug, an in vivo QT assessment is made. Depending on the in vivo outcome, additional non-clinical data may be collected, for example, data from an in vitro action potential assay. These data can then be collated on a single plot of free drugs levels against effects. The integrated risk assessment can then be completed by factoring in an estimate of the highest free drug levels in the plasma to give clinical efficacy along with an appreciation of the intended indication. The bold is to emphasize the integration of all relevant data.