Cardiotoxicity: Issues, Technologies, and Solutions for the Future

By Nick Miller, PhD

Chapter 1
CARDIAC ANATOMY AND PHYSIOLOGY
1.1. Anatomy of the Heart
1.2. The Cardiac Cycle
1.3. The Resting Potential
1.4. The Action Potential
1.5. Origin of the Heartbeat
1.6. Clinical Assessment of Cardiac Function
1.7. Cardiac Ion Channels
1.8. Summary

Chapter 2
CARDIOTOXICITY
2.1. “Directly Cardiotoxic” Drugs
2.2. Mechanism of Toxicity of “Directly Cardiotoxic” Drugs
  Anthracyclines/Anthracycline-Interacting Anticancer Drugs
  Other Anticancer Drugs
  Nonsteroidal Anti-inflammatory Drugs
  Other Drugs Associated with Direct Toxicity
2.3. “Direct Cardiotoxicity”
  Predisposing Factors
  Damage Limitation
2.4. “Proarrhythmic” Drugs
2.5. Mechanism of Cardiotoxicity of Proarrhythmic Drugs
  Molecular Targets of Proarrhythmic Drugs
  Drug Interactions with Ion Channels
  Arrhythmia Generation
2.6. Proarrhythmia
  Predisposing Factors
  Damage Limitation
2.7. Summary

Chapter 3
REGULATORY ENVIRONMENT AND INDUSTRY RESPONSE
3.1. History
3.2. ICH Guideline S7B: Preclinical QT Studies
3.3. ICH Guideline E14: Clinical QT Studies 
3.4. Other Regulatory Agency Documents
3.5. Regulatory Decision-Making
3.6. Industry Concerns
3.7. Summary

Chapter 4
ASSESSING DRUG-INDUCED CARDIOTOXICITY
4.1. Surrogate Markers for Proarrhythmia
  Measures of Ion Channel Flux
  Action Potential Morphology and Duration
  Dispersion of Action Potential Duration
        Temporal Dispersion of Action Potential Duration (Instability)
        Transmural Dispersion of Repolarization
        Spatial Dispersion of Repolarization
  QT Interval Prolongation
  Combinations of Measures
4.2. Preclinical Proarrhythmia Screening
  In Silico Approaches
  Single-Cell Methods
        Cell Types
        Non–Patch Clamp Single-Cell Assay
        Conventional Patch Clamping
        Automated Medium-/High-Throughput Patch Clamping
        Scanning Patch Clamping
  Multicell Methods
        Purkinje Fiber and Papillary Muscle Systems
        Ventricular Wedge
        Whole Heart Systems
               Langendorff Perfused Heart
               SCREENIT Perfused Rabbit Heart
  Future Developments in Multicellular In Vitro Systems
4.3. Preclinical Proarrhythmia Screening: In Vivo Methods
  Anesthetized Animals
  Conscious, Telemetrized Animals
  Predisposed Models
        Methoxamine-Sensitized Rabbits
        Canine Chronic Atrioventricular Block
        Canine Pharmacological IKs Block
        Other Models
4.4. Clinical Trials and Postmarketing Surveillance
  Low Frequency of Arrhythmia Complicates Trials
  Pharmacogenetics
  Measurements in the Trial Population
  Impact of QT Effects Discovered in Clinical Trials
4.5. Screening for “Direct” Cardiotoxicity
  Markers of Cardiac Damage
  Animal Models
4.6. Summary

Chapter 5
INDUSTRY ATTITUDES AND CARDIOTOXICITY SURVEY RESULTS
5.1. Previous Surveys
5.2. Insight Pharma Reports Cardiotoxicity Survey—December 2007
  Survey Population
  Analysis of Questionnaire Responses
        In Silico Methods
        In Vitro Methods
        In Vivo Methods
        Clinical Methods
5.3. Insight Pharma Reports Expert Interviews
  Survey Population
  Analysis of Interview Responses
        In Silico Methods
        In Vitro Methods
              Single-Cell Systems
              Multicell Systems
        In Vivo Methods
        Clinical Methods
        Views on the TQT Study
        Timing and Nature of Possible Changes to S7B or E14
              S7B
              E14
5.4. Summary
 
Chapter 6
COMMERCIAL ENVIRONMENT
6.1. Cardiotoxicity Screening Segment
6.2. Proarrhythmia Screening Product/Service Providers
6.3. Summary

Chapter 7
AN OPINION: THE FUTURE OF CARDIOTOXICITY SCREENING IN DRUG DEVELOPMENT
7.1. Proarrhythmia Screening
  Early-Stage Drug Development
  Late-Stage Drug Development
7.2. Screening for “Direct” Cardiotoxicity
  Chronic Cardiotoxicity
  Acute Cardiotoxicity
7.3. Summary

Appendix A
EXPERT INTERVIEWS
Charles Antzelevitch, PhD, Executive Director and Director of Research, Masonic Medical Research Laboratory, Utica, NY
Ernest D. Bush, PhD, Vice President and Scientific Director, Cambridge Healthtech Associates, Needham, MA (formerly Head of Non-clinical Drug Safety Department, Hoffmann-La Roche)
Marek Malik, MD, PhD, Professor of Cardiac Electrophysiology, St. George’s Hospital, University of London, UK
Umesh Patel, PhD, Director, R&D, Ion Channel Group, BioScience Division, Millipore UK, Cambridge, UK
Katya Tsaioun, PhD, President, Apredica, Watertown, MA
Benoit Tyl, MD, Medical Director, Europe, MDS Pharma Services/Centralized Cardiac Services

Appendix B
COMPANIES PROVIDING CARDIOTOXICITY SCREENING PRODUCTS OR SERVICES

Appendix C
PROFILES OF TOP 29 COMPANIES
Apredica
Aurora Biomed
AVIVA Biosciences
BioFocus (part of Galapagos)
bSys GmbH
Caliper Life Sciences (Xenogen subsidiary)
Cellectricon
Cellular Dynamics International
CEREP
ChanTest
Charles River Laboratories
Cyprotex
Cytocentrics
Cytoplex BioSciences
Essen Instruments
EvoTec
Flyion
Hondeghem Pharmaceutical Consulting
IonGate Biosciences GmbH
MDS Pharma Services (part of MDS Inc.)
Millipore
MultiChannel Systems GmbH
Nanion Technologies
Nerviano Medical Sciences
NeuroSolutions Ltd.
QTest Labs
RxGen
Sophion
Zenas Technologies

Appendix D
INSIGHT PHARMA REPORTS CARDIOTOXICITY SURVEY—DECEMBER 2007