Transcript Document

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