Cardiotoxicity: Issues, Technologies, and Solutions for the Future

By Nick Miller, PhD

FIGURES
Figure 1.1. Anatomy of the Human Heart
Figure 1.2. Typical Action Potential of a Cardiac Myocyte
Figure 1.3. Relationship Between Action Potential, ECG, and the Main Contributory Currents
Figure 1.4. Typical ECG Trace and Its Relationship to Major Myocyte Ion Currents
Figure 1.5. Structure of a Potassium-Specific Cardiac Ion Channel
Figure 2.1. Dispersion of Some hERG Mutations
Figure 3.1. Drug Label Amendments or Withdrawals Due to Drug-Associated Arrhythmia
Figure 4.1. Major Electrophysiological Events Known to Play a Role in TdP Generation
Figure 4.2. Summary of the Traditional Concept of Drug-Induced Torsadogenesis
Figure 4.3. Action Potential and ECG Relationships Between the 3 Ventricular Layers
Figure 5.1. Involvement in Cardiotoxicity Assessment
Figure 5.2. Response by Sector
Figure 5.3. Use of In Silico Methods to Assess TdP Liability
Figure 5.4. Timeframe for Acceptance of In Silico hERG-Binding Screening Data
Figure 5.5. In Vitro Single-Cell Systems Used
Figure 5.6. Additional Ion Channels Screened
Figure 5.7. In Vitro Multicell Systems Used
Figure 5.8. Timeframe for Acceptance of In Vitro Multicell Systems by Regulatory Authorities for Assessment of TdP Potential
Figure 5.9. Timeframe for Acceptance of In Vitro Signals by Regulatory Authorities as Valid Surrogate Markers of TdP Liability
Figure 5.10. Timeframe for Acceptance of HM/MT In Vitro Screening Systems as Providing Valid Data Regarding TdP Liability
Figure 5.11. In Vivo Models Used
Figure 5.12. Timeframe for Acceptance of In Vivo Signals by Regulatory Authorities as Valid Surrogate Markers of TdP Liability
Figure 5.13. Necessity of QT/QTc Study When There Is No Evidence of TdP Liability
Figure 5.14. Effect of Intensive Late-Phase Cardiac Studies on Withdrawal of Drugs from Development
Figure 6.1. Split of Activities of Relevant Companies
Figure 6.2. Public/Private Status of Relevant Companies
Figure 6.3. Activity Split Among the Top 29 Companies
Figure 6.4. Public/Private Status of the Top 29 Companies
Figure 6.5. Product/Service Split Among the Top 29 Companies
Figure 6.6. Product/Service Strategic Space of Top 29 Companies

TABLES
Table 1.1. Currents that Contribute to the Cardiac Action Potential
Table 2.1. “Directly Cardiotoxic” Drug Classes and Associated Adverse Events
Table 2.2. Potentially Proarrhythmic Drugs
Table 2.3. Drugs That Can Interact with hERG
Table 3.1. Drug Label Amendments or Withdrawals Due to Drug-Associated Arrhythmia
Table 6.1. Top Providers of Products/Services for Proarrhythmia Screening

APPENDIX FIGURES
Fig 1A. Is your organization involved in cardiotoxicity assessments and/or in the design or conduct of QT/QTc clinical studies?
Fig 2A. Please classify your organization
Fig 3A. Does your organization use in silico methods for assessing Torsades de Pointes liability of development stage compounds?
Fig 4A. What is your in silico methodology designed to screen out?
Fig 5A. What does your in silico methodology usually identify?
Fig 6A. When do you think the regulatory authorities will accept in silico hERG-binding screening data as a substitute for in vitro hERG-binding data?