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Cited by 117Cardiac electrophysiology and arrhythmiasAnimal testing and alternativesPharmaceutical studies and practices

Methods of collecting and evaluating non-clinical cardiac electrophysiology data in the pharmaceutical industry: results of an international survey

Hammond, T·2001·Cardiovascular Research
DOI 10.1016/s0008-6363(00)00310-2
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Abstract

OBJECTIVE: To assess current practice in the pharmaceutical industry for assessing the potential for QT interval prolongation by non-cardiovascular medicinal products. METHODS: The survey was based on responses from the Toxicology and (Safety) Pharmacology laboratories (a total of 74 laboratories) of 54 companies based in Europe, Japan/Asia and the USA, received between January and March 1999. RESULTS: All 54 companies conducted preclinical in vivo electrocardiography (EGG) evaluation of new active substances (NASs). Thirty of these companies also conducted in vitro cardiac electrophysiology studies on their compounds. The majority of in vivo work was done in conscious beagle dogs. There was no consistency within the industry in defining the magnitude of change in QT interval that is considered biologically important. Most companies considered a change greater than 10% to be important, although the design of the studies suggested that group sizes used may not give sufficient statistical power to detect this size of change. Bazett's formula was used by 41% of laboratories to correct QT for changes in heart rate, despite the fact that this formula is generally deemed to be unsuitable for use in dogs. For studies in anaesthetised dogs, the majority of laboratories used barbiturate anaesthesia, but researchers should be aware of the effects of this and some other anaesthetic agents on QT interval. As for in vitro cardiac electrophysiology, there was wide diversity in the testing methodologies, particularly with regard to the test species and tissue type. As with QT prolongation, there was no consensus on the degree of action potential prolongation to cause concern. For both in vitro and in vivo testing, the majority of companies tested a minimum of three dose (or concentration) levels in order to ascertain any dose-response relationship. CONCLUSIONS: The survey provides a snapshot of the practice in the industry prior to any internationally-agreed consensus on the most effective and efficient approaches to minimising the risk of QT prolongation by new drugs in man. It must be stated that for any given methodology, the 'majority view' in the industry is not necessarily best practice.

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  • Three separate surveys of the pharmaceutical industry revealed that canine was the most commonly used animal model for evaluating QT interval prolongation of novel compounds.

    “Three separate surveys of the pharmaceutical industry revealed that canine was the most commonly used animal model for evaluation and determination of QT interval prolongation of novel compounds (Friedrichs, Patmore, & Bass, 2005; Hammond, et al., 2001; Lindgren, et al., 2008).”

    From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Hammond, et al., 2001

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Authors
Hammond, T.
Affiliations
AstraZeneca (United Kingdom) (GB)
Corresponding author
Hammond, T
ORCID
Hammond, T
Venue
Cardiovascular Research
Publisher
Oxford University Press (OUP)
Published
2001-03
Volume
49
Issue
4
Pages
741-750
ISSN
0008-6363 (ISSN-L)
DOI
10.1016/s0008-6363(00)00310-2
OpenAlex
W2004833283
Cited by
117
References
24
Citations by year
2026: 1 · 2024: 4 · 2023: 1 · 2021: 1 · 2020: 1 · 2019: 4 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 1 · 2013: 10 · 2012: 3
FWCI
7.07
Type
journal article
Language
en
Open access
closed
Locations
  • Cardiovascular Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Keywords
QT prolongation, cardiac safety assessment, beagle dogs, Bazett formula, barbiturate anesthesia, action potential prolongation, dose-response relationship, drug safety
MeSH terms
Action Potentials, Animals, Animals, Laboratory, Data Interpretation, Statistical, Dogs, Dose-Response Relationship, Drug, Drug Industry, Drug Evaluation, Preclinical, Electrocardiography, Papillary Muscles, Purkinje Fibers, Research Design, Models, Animal, Rats, In Vitro Techniques

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