Cardiovascular Toxicology

, 11:285

Supplemental Studies for Cardiovascular Risk Assessment in Safety Pharmacology: A Critical Overview

  • Sandra Picard
  • Sonia Goineau
  • Philippe Guillaume
  • Joël Henry
  • Jean-Luc Hanouz
  • René Rouet
Article

DOI: 10.1007/s12012-011-9133-z

Cite this article as:
Picard, S., Goineau, S., Guillaume, P. et al. Cardiovasc Toxicol (2011) 11: 285. doi:10.1007/s12012-011-9133-z

Abstract

Safety Pharmacology studies for the cardiovascular risk assessment, as described in the ICH S7A and S7B guidelines, appear as being far from sufficient. The fact that almost all medicines withdrawn from the market because of life-threatening tachyarrhythmias (torsades-de-pointes) were shown as hERG blockers and QT interval delayers led the authorities to focus mainly on these markers. However, other surrogate biomarkers, e.g., TRIaD (triangulation, reverse-use-dependence, instability and dispersion of ventricular repolarization), have been identified to more accurately estimate the drug-related torsadogenic risk. In addition, more attention should be paid to other arrhythmias, not related to long QT and nevertheless severe and/or not self-extinguishing, e.g., atrial or ventricular fibrillation, resulting from altered electrical conduction or heterogeneous shortening of cardiac repolarization. Moreover, despite numerous clinical cases of drug-induced pulmonary hypertension, orthostatic hypotension, or heart valvular failure, few safety investigations are still conducted on drug interaction with cardiac and regional hemodynamics other than changes in aortic blood pressure evaluated in conscious large animals during the core battery mandatory studies. This critical review aims at discussing the usefulness, relevance, advantages, and limitations of some preclinical in vivo, in vitro, and in silico models, with high predictive values and currently used in supplemental safety studies.

Keywords

Safety Pharmacology Cardiovascular risk Proarrhythmic risk QT interval Hemodynamics Preclinical studies 

Abbreviations

ABP

Arterial blood pressure

AF

Atrial fibrillation

AP

Action potential

APD90

Action potential duration at 90% of repolarization

AV

Atrio-ventricular

DAD

Delayed-after-depolarization

EAD

Early-after-depolarization

ECG

Electrocardiogram

ERP

Effective refractory period

GLP

Good laboratory practice

hERG

Human ether-a-gogo related gene

ICaL

L-type calcium current

IK1

Inward rectifier potassium current

IKr

Rapid component of the delayed rectifying potassium current

IKs

Slow component of the delayed rectifying potassium current

IKto

Transient outward potassium current

INa

Sodium current

LVP

Left ventricular pressure

PK/PD

Pharmacokinetic/pharmacodynamic

pVT

Polymorphic ventricular tachycardia

TdP

Torsades-de-pointes

TQT

Thorough QT

VF

Ventricular fibrillation

VT

Ventricular tachycardia

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Sandra Picard
    • 1
  • Sonia Goineau
    • 2
  • Philippe Guillaume
    • 2
  • Joël Henry
    • 3
  • Jean-Luc Hanouz
    • 1
  • René Rouet
    • 1
  1. 1.Groupe Coeur et Ischémie, EA 3212Université de CaenCaenFrance
  2. 2.Porsolt and Partners PharmacologyZ.A. de GlatignéLe Genest-Saint-IsleFrance
  3. 3.UMR 100 IFREMER-UCBN, Physiologie et Ecophysiologie des Mollusques MarinsUniversité de CaenCaenFrance

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