Abstract

The electrical activity of the heart, characterised by the QT interval on an electrocardiogram (ECG), serves as a crucial parameter for evaluating cardiac health. Variations in the QT interval, particularly when corrected for heart rate using Fridericia’s formula (QTcF), have long been of interest in cardiology and play a pivotal role in assessing cardiac safety in clinical trials. Understanding the influence of meals given at different times on QTcF intervals is essential for the accurate execution of Thorough QT (TQT) studies. Moreover, it has been proposed that this meal-related QT interval shortening could serve as a valuable indicator of assay sensitivity in TQT studies or even as a potential integration of TQT investigations into in Phase I/II studies.

This study explores the impact of meals on QTcF intervals, specifically in the context of pharmacodynamic studies and TQT investigations. The primary goal is to gain insights into how different meals and baseline calculations affect QTcF changes and their potential implications for cardiac health and the risk of arrhythmias. Recent research has begun shedding light on the intricate relationship between meal composition, timing, and QTcF alterations. Several studies have investigated the effects of various nutrients, such as carbohydrates, fats, and proteins, on QTcF duration, as well as the implications of postprandial changes. These investigations have unveiled the complex interplay between dietary components and the cardiovascular system, raising essential questions about how our dietary choices may influence cardiac electrophysiology.

In this comprehensive meta-analysis, we analyse data from nine studies, all conducted in accordance with Good Clinical Practice and ethical standards. These studies were approved by Ethics Committees and Regulatory authorities. Our analysis focuses on ECG assessments, involving the use of 12-lead ECGs recorded electronically and evaluated by certified cardiologists. We apply the Fridericia formula for QT correction (QTcF), as it has been shown to provide more accurate results across different heart rates compared to other correction methods.

Our findings confirm existing literature into the impact of meals on QTcF intervals. We observe a consistent shortening of QTcF following breakfast, exceeding 5 milliseconds, which aligns with the positive control requirement defined by ICH E14, thus demonstrating the validity of our approach. In contrast, the effect of lunch is consistently less than 5 milliseconds across various timepoints and studies, indicating differences in the meal-related QTcF changes.

Furthermore, our analysis incorporates gender-based assessments, showing that women exhibit a smaller effect than men, which is significant for breakfast and the fasted condition. These results suggest that the observed QTcF effect post-breakfast is a combination of the meal itself and factors unique to the initial day of a study. This insight holds potential for improving the design and interpretation of cardiac safety studies, particularly in Phase I investigations, and may offer the opportunity to explore the removal of positive control agents like Moxifloxacin, thereby reducing exposure to harmful challenge agents and contributing to the global effort to combat antimicrobial resistance (AMR).

In conclusion, this meta-analysis advances our understanding of meal-induced QTcF changes and their significance in cardiac safety assessment, offering the prospect of more efficient and patient-focused drug development practices. This not only contributes to enhanced safety but also supports the reduction of antibiotic consumption, a key element in the global fight against AMR.