The figure below depicts the physiologic model for the QT-RR interval relationship underlying the QTbtb method. This highly dynamic state that occurs from beat-to-beat allows humans to live within their own unique QT-RR boundary influenced by many different conditions of autonomic-mediated change such as eating, sleeping, and exercise or by disease states that alter QT-RR heterogeneity. Holter acquired data plotted from long-term monitoring produces large QT-RR data “clouds” that can easily span over 1000 ms in the RR interval range and 70 ms in QT magnitude in any given individual. Conventional QTc methodology, adopted for drug safety evaluation by the ICH E14 guidance, however, assumes the RR relationship in a normal individual can be represented by a line. This assumption, while simplifying computation, grossly misrepresents the underlying physiologic phenomena. The conventional QTc method applies a variety of linear formulae to correct for heart rate changes when comparing QT values sampled at baseline and on-drug. The actual QT interval often is misrepresented because delayed cardiac repolarization cannot be differentiated – in this linear formula – from autonomic-mediated responses such as reflex tachycardia and reflex bradycardia. (see shaded areas in Fig. 1 above and below Fridericia curve). In the QTbtb method the normal (unstressed) autonomic-mediated QT-RR boundary is first established as the upper confidence bounds (or lower bounds for QT shortening) before drug administration. The area below this boundary represents a safe cardiac physiological limit for QT change. QT prolongation beyond this limit may represent drug-induced delayed repolarization associated with some degree of as yet undefined arrhythmogenic risk.

Figure 1. Normal dynamic QT-RR interval relationship (black dotted-line forming asymmetric cloud) encompasses autonomic reflex responses such as tachycardia (RT) and bradycardia (RB) with hysteresis. The statistical outer boundary of the normal cloud is defined as the upper 95% confidence bounds (solid black line). QT prolongation of undefined arrhythmogenic risk (red shaded area) occurs when exceeding the 95% confidence bounds of QT intervals during unstressed autonomic influence. The Fridericia correction factor (blue diagonal line) applied to the resting QT-RR interval relationship overcorrects dynamic responses in the normal range (striped area above correction line and below 95% confidence bounds) or underestimates QT prolongation at slow heart rates (shaded area above 95% confidence bounds but below Fridericia correction line). The over-correction leads to a high probability of a false-positive or overestimated QTc prolongation finding for drugs that affect the autonomic state by lowering blood pressure and inducing reflex tachycardia. Conversely, the under-correction by Fridericia leads to a lower, but still significant probability of a false-negative or underestimated QTc prolongation finding for drugs that increase the blood pressure and induce reflex bradycardia.

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