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Prolongation of repolarization in pre-clinical investigations and phase I/II clinical trials: what should be done?

G. Sponer*

Institute of Pharmacology and Toxicology, Ruprecht-Karls-University Heidelberg, Mannheim, Germany

* Correspondence: G. Sponer, Institute of Pharmacology and Toxicology, Ruprecht-Karls-University Heidelberg, Maybachstrasse 14-16, D-68169 Mannheim, Germany.

Abstract

In the past, some non-cardiovascular drugs have been identified as prolonging repolarization and evoking torsade de pointes. Concerns prompted the health authorities to request detailed investigations targeted on this issue. In particular, in vitro and in vivo pre-clinical studies are regarded as mandatory in order to assess properly the potential risk of new compounds. However, appropriate assessment is only possible if the methods used are standardized and validated, which cannot currently be completely guaranteed. Additionally, a suitable threshold should also be specified in pre-clinical test systems. If some findings indicate prolongation of repolarization, further investigations are needed in order to evaluate the potential risk or to get more insight into the mode of action. However, withdrawal of the compound from further development at any stage is another alternative in order to spare resources and to avoid regulatory problems. In any case, a proper evaluation of the benefit-risk ratio is mandatory when findings indicate that a new compound may prolong repolarization.

Key Words: Action potential • QT prolongation • drug development


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