session iii – models of tdp proarrhythmia co-chairs: wilhelm haverkamp and marc vos rapporteurs:...
TRANSCRIPT
![Page 1: Session III – Models of TdP Proarrhythmia Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach](https://reader035.vdocuments.us/reader035/viewer/2022072006/56649d095503460f949db6e5/html5/thumbnails/1.jpg)
Session III – Models of TdP
Proarrhythmia
Co-Chairs: Wilhelm Haverkamp and Marc Vos
Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach
Moving Towards Better Predictors of Drug-Induced Torsade de Pointes (TdP) Workshop
![Page 2: Session III – Models of TdP Proarrhythmia Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach](https://reader035.vdocuments.us/reader035/viewer/2022072006/56649d095503460f949db6e5/html5/thumbnails/2.jpg)
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
![Page 3: Session III – Models of TdP Proarrhythmia Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach](https://reader035.vdocuments.us/reader035/viewer/2022072006/56649d095503460f949db6e5/html5/thumbnails/3.jpg)
Breakout Session III Report
• Identification of consensus issues
• Development of priorities for next steps
![Page 4: Session III – Models of TdP Proarrhythmia Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach](https://reader035.vdocuments.us/reader035/viewer/2022072006/56649d095503460f949db6e5/html5/thumbnails/4.jpg)
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
![Page 5: Session III – Models of TdP Proarrhythmia Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach](https://reader035.vdocuments.us/reader035/viewer/2022072006/56649d095503460f949db6e5/html5/thumbnails/5.jpg)
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)
TdP Proarrhythmia Models
![Page 6: Session III – Models of TdP Proarrhythmia Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach](https://reader035.vdocuments.us/reader035/viewer/2022072006/56649d095503460f949db6e5/html5/thumbnails/6.jpg)
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
![Page 7: Session III – Models of TdP Proarrhythmia Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach](https://reader035.vdocuments.us/reader035/viewer/2022072006/56649d095503460f949db6e5/html5/thumbnails/7.jpg)
• Diseased animal model
• Intact animal
• Isolated heart
• Isolated tissue and/or wedge
• Single cells
A multi-faceted testing strategy employing test systems
of increasing complexity (addressing several
parameters) is proposedCom
plex
ity
![Page 8: Session III – Models of TdP Proarrhythmia Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach](https://reader035.vdocuments.us/reader035/viewer/2022072006/56649d095503460f949db6e5/html5/thumbnails/8.jpg)
• Repolarization times (local and global)
including rate dependence
• Spatial dispersion
• Temporal dispersion
• EADs
• Arrhythmias
Co
mp
lexi
ty
Parameters to be recorded include:
![Page 9: Session III – Models of TdP Proarrhythmia Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach](https://reader035.vdocuments.us/reader035/viewer/2022072006/56649d095503460f949db6e5/html5/thumbnails/9.jpg)
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
![Page 10: Session III – Models of TdP Proarrhythmia Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach](https://reader035.vdocuments.us/reader035/viewer/2022072006/56649d095503460f949db6e5/html5/thumbnails/10.jpg)
At least two species needed for validation purposes
• Rabbit as species of choice
• Dogs proposed as second species
Non human primates may be considered when
metabolically closer related to humans
![Page 11: Session III – Models of TdP Proarrhythmia Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach](https://reader035.vdocuments.us/reader035/viewer/2022072006/56649d095503460f949db6e5/html5/thumbnails/11.jpg)
We like to thank the session III
participants for their contributions
and enthusiastic discussions.