Moving Towards Better Predictors of Torsades des Pointes (TdP) Workshop

On November 2-3, 2005, the HESI Cardiovascular (CV) Pro-Arrhythmia Models Project Committee hosted a workshop in Crystal City, VA.  The workshop was organized to develop a better fundamental understanding of the emerging science, trends, and methods for predicting drug-induced TdP.  The specific objectives for the workshop included identifying the underlying mechanisms for drug-induced TdP, evaluating emerging non-clinical methodologies for predicting drug induced TdP, and identifying short and long-term priorities for developing better predictors for drug-induced TdP.  For more information on this workshop click on the above linked title.

Background

Delayed ventricular repolarization (QT interval prolongation) is a common feature of compounds associated with Torsade de Pointes (TdP) in humans.  Consequently, QT prolongation is a known risk factor for TdP.  TdP is a dangerous cardiac arrhythmia that can degenerate to ventricular fibrillation and lead to sudden death.  The drugs associated with TdP include a broad range of pharmacological classes, including antiarrhythmic, antihistamine, antibiotic, antipsychotic and others.  Our understanding of the mechanisms for drug-induced TdP is limited.

The ILSI Health and Environmental Sciences Institute (HESI) hosted an international workshop in June of 2003 to identify non-clinical methods and methodologies that are appropriate for assessing ventricular repolarization delay, and QT interval prolongation.  An additional goal for the workshop was to consider how those assays can be used collectively to develop an effective and practical risk assessment strategy.  While the workshop was effective in demonstrating the utility of established non-clinical methods for evaluating QT prolongation, the need to develop a better fundamental understanding of the mechanistic basis for drug-induced TdP and identify improved predictors of potential cardiotoxic drugs were important recommendations that emerged from the workshop discussions.

Given the limited information available regarding the relationship between risk factors of arrhythmia and drug-induced TdP, a critical need exists to identify models and methodologies that would facilitate a direct assessment of the probability of a compound eliciting TdP in humans. As a follow-up to that workshop, HESI is hosting a second workshop November 2-3, 2005 in Crystal City, Virginia to explore the underlying molecular and cellular mechanisms of drug-induced TdP, the utility of pro-arrhythmia models for predicting pro-arrhythmic risk, with the goal of identifying areas of investigation which may lead to models and methodologies that more accurately identify the risk posed by an experimental compound.

Workshop Objectives

The primary objectives for the workshop are to develop a better fundamental understanding of the emerging science, trends, and methods and methodologies that relate to predicting drug-induced TdP.  Specific objectives for the workshop include:

• Identify the underlying (known or novel) mechanisms for drug-induced TdP arrhythmia to develop better tools for identifying drugs at risk;
• Evaluate and assess emerging non-clinical methodologies for predicting drug induced TdP.
• Identify biomarkers in non-clinical studies that may be applied to clinical testing for drug-induced arrhythmia
• Identify the critical aspects of non-clinical and clinical methods of evaluating potential for drug-induced TdP in the context of public-health decision-making;
• Identify short and long-term priorities for developing better predictors for drug-induced TdP

Workshop Deliverables

• Identification from each of the breakout session of two to three focused areas of investigation that would help identify improved predictors of drug-induced TdP; indicating whether these are viewed as short or long term goals and the site(s) at which investigations can be pursued.
• Proceedings of speaker presentations, breakout session deliberations, and the recommendations of workshop participants.
• Review of workshop deliverables by the HESI - Cardiovascular Safety Subteam to determine the appropriateness of HESI pursuing a follow-up activity.

Workshop Materials

The format for the two-day workshop will include an initial day of plenary lectures followed by a second day of focused breakout sessions.  Participants will be invited to participate in breakout sessions to provide their expertise and interest.  The workshop begins on Wednesday, November 2, 2005 at 8:00 a.m. and concludes at 5:00 p.m. on Thursday, November 3, 2005.

The HESI Cardiovascular Safety Pro-Arrhythmia Models Project Committee will host a welcome reception on the evening of November 2, 2005 in the Windows Over Washington Restaurant at the Doubletree Hotel.  A continental breakfast and lunch will be provided to all participants on both days of the workshop. To download the workshop program click here.

This workshop has been organized to develop a fundamental understanding of the emerging science, trends, and methods for predicting drug-induced TdP.  Some of the specific objectives for the workshop include identifying the underlying mechanisms for drug-induced TdP, evaluating emerging non-clinical methodologies for predicting drug induced TdP, and identifying short and long-term priorities for developing better predictors for drug-induced TdP.

Click on the below links to access background documents for this workshop:

Session Focus Questions

• Session I - Molecular and Cellular Biology
• Session II - Dynamics of Periodicity
• Session II - Suggestions for Future Approaches
• Session III - Models of TdP Pro-Arrhythmia
• Session IV - Key Considerations for Demonstrating Model Utility

Speaker Key Messages

• Combined Speaker Key Messages.pdf

Suggested Background Reading

• Publications
• Workshop Program
• Workshop Participants List

Final Breakout Session Presentations (Power Point)

• Session I Summary
• Session II Summary
• Session III Summary
• Session IV Summary