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Moving Towards Better Predictors of Drug-Induced Torsade de Pointes (TdP) Workshop. Session III – Models of TdP Proarrhythmia. Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach. Presented data. J. Kramer, ChanTest: added MAPD-wave
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Moving Towards Better Predictors of Drug-Induced Torsade de Pointes (TdP) Workshop Session III – Models of TdP Proarrhythmia Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach
Presented data • J. Kramer, ChanTest: added MAPD-wave • alternans as parameter • C. Antzelevitch: spatial dispersion emphasized • as important parameter • B. Hamlin: heart failure rabbit model • S. Moise: inherited German shephard sudden • death dog model
Breakout Session III Report • Identification of consensus issues • Development of priorities for next steps
Identification of consensus issues • There is a need for in-vitro and in-vivo TdP • proarrhythmia models • A multi-faceted testing strategy that incorporates several parameters simultaneously is proposed that includes data derived from increasingly complex structures (ie. single cells to intact animal and pathological models) • Agreement that a multi-center validation study • is needed (eg: each model / method is to be tested in more than 1 laboratory) • At least two species needed for validation • purposes
TdP Proarrhythmia Models • Strategic Approach • A useful model should possess the following properties: • Provide adequate testing throughput to meet the users needs (e.g., in-vitro throughput comparable to manual patch-clamp techniques and in-vivo comparable to non-rodent telemetry studies) • Intact animal model should employ a conscious animal • Animal model should reproducibly develop spontaneous TdP • High sensitivity at clinical therapeutic dose (and • beyond)
There is a need for in-vitro and in-vivo TdP proarrhythmia models • Increase knowledge of arrhythmogenic • mechanisms (helps to identify new parameters of proarrhythmia) • Validated parameters might help to add value to • the QT (weak surrogate) parameter by • improving clinical prediction of proarrhythmia
A multi-faceted testing strategy employing test systems of increasing complexity (addressing several parameters) is proposed • Diseased animal model • Intact animal • Isolated heart • Isolated tissue and/or wedge • Single cells Complexity
Parameters to be recorded include: • Repolarization times (local and global) • including rate dependence • Spatial dispersion • Temporal dispersion • EADs • Arrhythmias Complexity
Agreement that multi-center validation study is needed • International • Blinded, standardized, reproducible based on preliminary investigations • (qualified locations) • Subcommittee appointed to coordinate with special attention to sensitivity and specificity, and selection of drugs
At least two species needed for validation purposes • Rabbit as species of choice • Dogs proposed as second speciesNon human primates may be considered when metabolically closer related to humans
We like to thank the session III participants for their contributions and enthusiastic discussions.