Investigation of the Potential of Clozapine to Cause Torsade de Pointes
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Adv Drug React Toxicol Rev 2002; 21 (4): 189-203 0964-198X/02/0004-0189/$25.00/0 © Adis International Limited. All rights reserved.
Investigation of the Potential of Clozapine to Cause Torsade de Pointes Barbara Warner1 and Peter Hoffmann2 1 Clinical Safety & Epidemiology, Novartis Pharma AG, Basel, Switzerland 2 Preclinical Safety, Novartis Pharma AG, Basel, Switzerland
Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Materials and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Preclinical In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1 Human ether-a-go-go Related Gene Channel . . . . . . . . . . . . . . . . 2.1.2 Purkinje Fibre Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3 Isolated Perfused Heart Preparations . . . . . . . . . . . . . . . . . . . . . . 2.1.4 Preclinical In Vivo Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Clozapine Database Searches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1 Studies in Healthy Volunteers . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2 Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3 Spontaneous Reports and Post-Marketing Surveillance Database Analysis 2.3 Thioridazine Database Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1 Spontaneous Reports Database Analysis . . . . . . . . . . . . . . . . . . . 2.4 Medline/Internet Literature Review . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Predictive Value of Preclinical Data . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Adverse Drug Reaction Database . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Literature Review of Clinical Data . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Limitations of This Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
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Antipsychotics are frequently associated with QTc interval prolongation, a proposed marker for vulnerability to fatal ventricular arrhythmias, e.g. torsade de pointes (TdP). Little has been published on this topic in relation to clozapine. The objectives of this review were to: (i) calculate the frequency of QTc interval prolongation, T-wave abnormalities, TdP, v
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