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

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

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

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

• 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

• Repolarization times (local and global)

including rate dependence

• Spatial dispersion

• Temporal dispersion

• EADs

• Arrhythmias

Co

mp

lexi

ty

Parameters to be recorded include:

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 species

Non 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.