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

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

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