Novel approaches to assessing cardiac safety--proceedings of a workshop: regulators, industry and academia discuss the future of in silico cardiac modelling to predict the proarrhythmic safety of drugs.

摘要

Current testing for proarrhythmic potential of drugs relies on determining their effect on the QT interval of the ECG. Because QT prolongation is frequently associated with blockade of the human ether-a-go-go related gene (hERG) channel, the International Conference on Harmonization (ICH) S7B guideline recommends an hERG inhibition assay as the first proxy for identifying such potential risk. Since hERG assays are relatively cheap and rapid, pharmaceutical companies invariably rely on them for early-stage triage of new compounds. The TQT (Thorough QT) study, the backbone of clinical cardiac safety testing under ICH E14, is a blunt instrument with a poor positive predictive value. Candidate compounds suspected or shown to prolong the QT interval may be rejected out of hand or attract restrictive labelling.