The continuing evolution of torsades de pointes liability testing methods: is there an end in sight?

Area of Science:

• Cardiovascular Pharmacology
• Drug Safety and Toxicology
• Electrophysiology

Background:

• Drug-induced torsades de pointes (TdP) is a potentially lethal cardiac arrhythmia linked to adverse drug reactions affecting heart repolarization.
• Existing preclinical models for predicting TdP liability lack validation, necessitating the use of surrogate biomarkers like QT interval duration.
• Regulatory guidelines mandate safety screening for new drugs, but the absence of definitive preclinical TdP models presents challenges.

Purpose of the Study:

• To evaluate the limitations of current preclinical models used for assessing drug-induced TdP liability.
• To propose improvements in the integrated risk assessment (IRA) approach to better predict TdP risk.
• To suggest alleviating regulatory barriers by enhancing the validation and deployment of existing and novel preclinical models.

Main Methods:

• Review of current regulatory guidelines (ICH S7A and S7B) for drug-induced TdP assessment.
• Analysis of commonly employed preclinical models, including hERG gene assays, canine ECGs, rabbit ventricular wedge preparations, Langendorff hearts, and Purkinje fibers.
• Discussion of the concept of TdP as a multicausal event and its implications for risk assessment.

Main Results:

• No single validated preclinical model exists with TdP incidence as a hard endpoint, leading to reliance on surrogate biomarkers and complementary assays.
• The integrated risk assessment (IRA) approach, ideally combining hERG assays and canine ECGs, is supplemented by in vitro assays, but validation remains limited.
• Strict regulatory guidelines, while reducing proarrhythmic compounds, have also led to a decrease in the number of new chemical entities (NCEs) pursued in development.

Conclusions:

• Drug-induced TdP is a complex, multicausal event, meaning a positive result in one model does not guarantee proarrhythmia.
• Current preclinical models for TdP risk assessment require further validation and acceptance to improve predictive accuracy.
• Enhancing the integrated risk assessment approach through better model validation and development is crucial for overcoming regulatory hurdles and facilitating drug development.