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Preclinical cardio-safety assessment of torsadogenic risk and alternative methods to animal experimentation: The inseparable twins

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Abstract

The last decade has been marked by the withdrawal from the market of several medicines whose use in patients has been associated with the development of torsade de pointes (TdP), a potentially life-threatening polymorphic tachycardia. In a few cases, TdP can degenerate into ventricular fibrillation and lead to sudden death, thus constituting a real problem of public health. The recently finalized ICH S7B guideline defines the prolongation of the QT interval on the electrocardiogram as the best biomarker for predicting the torsadogenic risk of a given compound. However, a growing body of evidence suggests that drugs’ torsadogenic potential may not necessarily be proportional to their ability to prolong the QT interval. It is a dynamic combination of multiple predisposing factors and components rather than a single particular event that can trigger this particular tachycardia. Following recommendations of the guideline, pharmaceutical companies have intensively implemented methodologies to assess the possible risk of QT prolongation and TdP in humans. The main problem in cardiac safety pharmacology is how best to combine the capabilities of different methodologies with their strengths and limitations in order to detect the potential of one molecular entity to induce a lethal arrhythmia of very low clinical incidence. This publication will review the current methodologies, focusing on the alternative methods to animal experimentation, including an overview of cardiac modeling.

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Abbreviations

EADs:

early afterdepolarizations

hERG:

human ether-à-go-go-related gene K+ channel

IC50 :

concentration that reduces the hERG tail current by 50%

ICH:

international conference for harmonization

IKr:

rapidly-activating delayed outward rectifier potassium current

LQTS:

long QT syndrome

TdP:

torsade de pointes

TI:

therapeutic index

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Authors and Affiliations

  1. Novartis Pharma AG, Development, Safety Profiling & Assessment, Safety Pharmacology, Basel, Switzerland

    B. M. Dumotier

  2. Novartis Pharma AG, Clinical Development & Medical Affairs, Modeling and Simulation, East Hanover, New Jersey, USA

    A. V. Georgieva

  3. Novartis Pharma AG, Development/SP&A, MUT.2881. 203, CH 4002, Basel, Switzerland

    B. M. Dumotier

Authors
  1. B. M. Dumotier
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  2. A. V. Georgieva
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Correspondence to B. M. Dumotier.

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Dumotier, B.M., Georgieva, A.V. Preclinical cardio-safety assessment of torsadogenic risk and alternative methods to animal experimentation: The inseparable twins. Cell Biol Toxicol 23, 293–302 (2007). https://doi.org/10.1007/s10565-006-0882-6

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  • DOI: https://doi.org/10.1007/s10565-006-0882-6

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