Strategies to reduce the risk of drug-induced QT interval prolongation: a pharmaceutical company perspective.
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.
Pollard
C E
CE
AstraZeneca R&D Alderley Park, Safety Assessment UK, Macclesfield, Cheshire, UK. Chris.Pollard@astrazeneca.com
Valentin
J-P
JP
Hammond
T G
TG
D000818:Animals; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004345:Drug Industry; D064420:Drug-Related Side Effects and Adverse Reactions; D023381:Endpoint Determination / Q000379:methods; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D018570:Risk Assessment / Q000379:methods
D051638:Ether-A-Go-Go Potassium Channels