Session II – Dynamics of Periodicity

1. Session II – Dynamics of Periodicity • Chair • Derek Leishman • Rapportuers • Dianne Garnes and Jean-Pierre Valentin

2. Session II – Dynamics of Periodicity • Other issues such as non-TdP type arrhythmias are involved. However, they are outside the scope of this workshop and should be addressed elsewhere. • First step may be to understand the scope of the issue • Gap of knowledge: • Between animal versus human physiology / pharmacology • Focus on identifying patient population (e.g., genetic predisposition) • Understanding the dynamics of the ECG associated with TdP

3. Session II – Dynamics of Periodicity • Questions & issues • Descriptions of QT dynamics – determine succinct ways to summarize, quantify and describe the dynamics of QT • Contrast the QT dynamics under normal conditions, conditions of autonomic perturbation and under the conditions which precede pro-arrhythmia • Discuss the models and methods by which the dynamics of QT may be determined in animals and in man: choice of species, data collection methods, data analysis methods • Identify a limited series of studies which could be conducted to illustrate; (a) the dynamics of QT periodicity under normal conditions, (b) under conditions of altered periodicity not thought to be proarrhythmic e.g., some autonomic perturbations, (c) in the presence of a QT prolonging agent associated with TdP and (d) in the presence of an agent which prolongs QT but is not thought to be proarrhythmic.

4. Session II – Dynamics of Periodicity • Descriptions of QT dynamics – determine succinct ways to summarize, quantify and describe the dynamics of QT • Not satisfied by current parameters QT/QTc • 2 types of compounds of interest • Small increase in QT • Indirect effect on cardiac repolarisation (autonomic system) • Direct effect but safe ? • Large increase in QT • But safe (e.g. amiodarone) • How do you go forward • Alternatives which could be considered / validated • QT / TQ or QT / RR relationship • Beat to beat variability • Morphology / shape of ECG waves (T & U)

5. Session II – Dynamics of Periodicity • Discuss the models and methods by which the dynamics of QT may be determined in animals and in man: choice of species, data collection methods, data analysis methods • Consideration for model • Must be predictive • Species – gap beyond dog (e.g., Monkey) • Susceptibility to TdP in animal models • Single vs chronic exposure • Dose response vs exposure • Reproducibility / Intra-individual comparison • Transferable to man

6. Session II – Dynamics of Periodicity • Models &methods con’t.: • Test compounds • In discussion with FDA, CHMP, PMDA • Non-IKr QT prolongers • Range of IKr blockers • (Categories as per Redfern et al. 2003; Webster et al., 2002) • Non-“Big GUNS” ! • With “Thorough QT/QTc” study

7. Session II – Dynamics of Periodicity • Identify a limited series of studies which could be conducted to illustrate; (a) the dynamics of QT periodicity under normal conditions, (b) under conditions of altered periodicity not thought to be proarrhythmic e.g., some autonomic perturbations, (c) in the presence of a QT prolonging agent associated with TdP and (d) in the presence of an agent which prolongs QT but is not thought to be proarrhythmic. • Comparison of different analysis of continuously recorded ECGs data across species • Beat to beat variability of QT, QT-TQ; T / U waves morphology