Some people are born with prolonged QT interval, but others have prolonged QT interval thrust upon them – by medicines that affect cardiac repolarisation. QT prolongation predisposes to a disorganised heart rhythm called torsade de pointes, which can degenerate into ventricular fibrillation and death.
Several valuable drugs have been withdrawn from the market, or have had their use greatly restricted, because they can prolong QT interval and are associated with a risk of sudden death. Examples include prenylamine, terfenadine, astemizole, cisapride, and sertindole.
Regulatory authorities now expect to see a thorough QT trial – a rigorous assessment of an IMP’s potential to prolong QT interval – even if preclinical work shows no cardiac problems. At HMR, we’ve successfully completed many definitive thorough QT trial. We use industry-standard Mortara ECG machines to record high-quality digital 12-lead ECGs, which can be coded and analysed ‘blind’ by the sponsor’s choice of specialist contractor, anywhere in the world. We capture the 24-h ambulatory ECG (Holter) using the ELA SyneFlash system, which records continuous 12-lead ECG. SyneFlash allows continuous beat-to-beat automated measurement of QT interval and hourly estimation of mean QT, with immediate online analysis of relationships between QT and RR intervals. In our definitive QT studies, we use repeat-dose regimens to achieve steady state.
We include a positive control, such as moxifloxacin, or a CYP3A4 inhibitor, such as itraconazole. We maximise safety by keeping the subjects resident in our wards: our 16-channel Spacelabs ECG telemetry system allows us to monitor them continuously throughout the research facility. We’ve done many QT studies of new and existing medicines. Our track record shows that we can give sponsors the thorough QT study data that the regulators demand – safely, securely, and to strict timelines.
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