Assessment of the sensitivity of detecting drug-induced QTc changes using subject-specific rate correction

Abstract

AimsTo quantify the sensitivity of QT heart-rate correction methods for detecting drug-induced QTc changes in thorough QT studies. MethodsTwenty-four-hour Holter ECGs were analyzed in 66 normal subjects during placebo and moxifloxacin delivery (single oral dose). QT and RR time series were extracted. Three QTc computation methods were used: (1) Fridericia's formula, (2) Fridericia's formula with hysteresis reduction, and (3) a subject-specific approach with transfer function-based hysteresis reduction and three-parameter non-linear fitting of the QT–RR relation. QTc distributions after placebo and moxifloxacin delivery were compared in sliding time windows using receiver operating characteristic (ROC) curves. The area under the ROC curve (AUC) served as a measure to quantify the ability of each method to detect moxifloxacin-induced QTc prolongation. ResultsMoxifloxacin prolonged the QTc by 10.6±6.6ms at peak effect. The AUC was significantly larger after hysteresis reduction (0.87±0.13 vs. 0.82±0.12, p<0.01) at peak effect, indicating a better discriminating capability. Subject-specific correction further increased the AUC to 0.91±0.11 (p<0.01 vs. Fridericia with hysteresis reduction). The performance of the subject-specific approach was the consequence of a substantially lower intra-subject QTc standard deviation (5.7±1.1ms vs. 8.8±1.2ms for Fridericia). ConclusionThe ROC curve provides a tool for quantitative comparison of QT heart rate correction methods in the context of detecting drug-induced QTc prolongation. Results support a broader use of subject-specific QT correction.