© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Methods of collecting and evaluating non-clinical cardiac electrophysiology data in the pharmaceutical industry: results of an international survey
aSafety Assessment UK, AstraZeneca R&D Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
bCardiovascular Pharmacology, AstraZeneca R&D Mölndal, 431 83 Mölndal, Sweden
cAnimal Welfare Group, AstraZeneca R&D Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
dSafety Pharmacology Department, Safety Assessment UK, AstraZeneca R&D Charnwood, Loughborough, Leicestershire LE11 5RH, UK
eCovance Laboratories Limited, Otley Road, Harrogate, North Yorks HG3 1PY, UK
fRegulatory Toxicology and International Outsourcing Department, GlaxoWellcome R&D, Park Road, Ware, Hens, SG12 0DP, UK
gDepartment of Cardiological Sciences, St George's Hospital Medical School, London, UK
* Corresponding author. Tel.: +44-1625-514-810; fax: +44-1625-513-779
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.
KEYWORDS EGG; Ion channels; Long QT syndrome; Purkinje fiber; Sudden death