An introduction to QT interval prolongation and non-clinical approaches to assessing and reducing risk.
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.
Safety Assessment UK, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, UK. chris.pollard@astrazeneca.com
Chris E
CE
Pollard
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N
Abi Gerges
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MH
Bridgland-Taylor
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Easter
T G
TG
Hammond
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JP
Valentin
D000818:Animals; D004285:Dogs; D015195:Drug Design; D064420:Drug-Related Side Effects and Adverse Reactions; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D018570:Risk Assessment / Q000379:methods; D016171:Torsades de Pointes / Q000139:chemically induced
D051638:Ether-A-Go-Go Potassium Channels