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Meal intake leads to a significant and prolonged increase in cardiac output to supply the splanchnic vasculature. A meal is associated with sympathetic activation of the cardiovascular system, and food ingestion is correlated with an increase in heart rate, an increase in cardiac stroke volume, and QTc interval shortening for up to 7 hours. Given the complexity of the system, one or several of many mechanisms could explain this observation. The shortening of the QTc interval was correlated with a rise of C-peptide following food ingestion, but the mechanisms by which C-peptide may be involved in the modulation of cardiac repolarization are still unknown. This shortening of the myocardial action potential caused by the ingestion of food was further investigated in the present study by measuring the QRS, J-T peak , and T peak -T end intervals in search of further clues to better understand the underlying mechanisms. A retrospective analysis was conducted based on data collected in a formal thorough QT/QTc study in which 32 subjects received a carbohydrate-rich "continental" breakfast, moxifloxacin without food, and moxifloxacin with food. We assessed the effect of food on T-wave morphology using validated algorithms for measurement of J-T peak and T peak -T end intervals. Our findings demonstrate that a standardized meal significantly shortened J-T peak for 4 hours after a meal and to a much lesser extent and shorter duration (up to 1 hour) prolonged the T peak -T end and QRS intervals. This suggests that the QTc shortening occurs mainly during phase 2 of the cardiac action potential. As there was no corresponding effect on T peak -T end beyond the first hour, we conclude that a meal does not interfere with the outward correcting potassium channels but possibly with Ca 2+ currents. An effect on mainly Ca 2+ aligns well with our understanding of physiology whereby an increase in stroke volume, as observed after a meal, is associated with changes in Ca 2+ cycling in and out of the sarcoplasmic reticulum during cardiac myocyte contraction., (© 2019, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Understanding the physiological fluctuations in the corrected QT (QTc) interval is important to accurately interpret the variations in drug-induced prolongation. The present study aimed to define the time course of the effect of moxifloxacin on the QT interval to understand the duration of the responses to moxifloxacin. This retrospective analysis was performed on data taken from a thorough QT 4-way crossover study with 40 subjects. Each period consisted of a baseline electrocardiogram (ECG) day (day -1) and a treatment day (day 1). On both days, ECGs were recorded simultaneously using 2 different systems operating in parallel: a bedside ECG and a continuous Holter recording. The subjects were randomized to 1 of 4 treatments: 5 mg and 40 mg of intravenous amisulpride, a single oral dose of moxifloxacin (400 mg), or placebo. Standardized meals, identical in all 4 periods, with similar nutritional value were served. Bedside ECG results confirmed that the moxifloxacin peak effect was delayed in the fed state and showed that the Fridericia corrected QT prolongation induced by moxifloxacin persisted until the end of the 24-hour measurement period. The use of continuous Holter monitoring provided further insight, as it revealed that the moxifloxacin effect on QTc was influenced by diurnal and nocturnal environmental factors, and hysteresis effects were noticeable. The findings suggested that moxifloxacin prolongs QTc beyond its elimination from the blood circulation. This is of relevance to current concentration-effect modeling approaches, which presume the absence of hysteresis effects., (© 2018, The American College of Clinical Pharmacology.)

A thorough QT/QTc study in healthy white Caucasian subjects demonstrated that rupatadine has no proarrhythmic potential and raised no cardiac safety concerns. The present phase 1 study aimed to confirm the cardiac safety of rupatadine in healthy Japanese subjects. In this randomized, double-blind, placebo-controlled study, 27 healthy Japanese subjects were administered single and multiple escalating rupatadine doses of 10, 20, and 40 mg or placebo. Triplicate electrocardiogram (ECG) recordings were performed on days -1, 1, and 5 at several points, and time-matched pharmacokinetic samples were also collected. Concentration-effect analysis based on the change in the QT interval corrected using Fridericia's formula (QTcF) from average baseline was performed. Data from the formal TQT study in white Caucasian subjects was used for a comparison analysis. The ECG data for rupatadine at doses up to 40 mg did not show an effect on the QTc interval of regulatory concern. The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a significant shortening of QTcF on days 1 and 5 four hours after a standardized meal. The data from this study exhibited no statistically significant differences in the QTc effect between Japanese and white Caucasian subjects., (© 2017, The American College of Clinical Pharmacology.)

Background: E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects., Methods: Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day)., Results: In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis., Conclusion: The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal., Trial Registration: EU Clinical Trials Register EudraCT 2010 020343 13.

In this randomized, double-blind, placebo controlled study, the safety of therapeutic (675 mg) and supra-therapeutic (2,700 mg) doses of nitazoxanide was evaluated in accordance with the ICH E14 guidelines. Fifty six (56) subjects participated in four treatment periods and received single doses of nitazoxanide 675 mg, nitazoxanide 2,700 mg, moxifloxacin 400 mg, or placebo. For 675 mg nitazoxanide, the largest change in QTcF from baseline was observed at 12 hours post-dose with a peak value of 1.6 ms (two-sided 90% CI: -0.3, 3.6 ms). The largest negative change in QTcF was observed at 1 hour post-dose (-2.7 ms with two-sided 90% CI: -4.5, -0.8 ms). The largest change in QTcF from baseline for 2,700 mg nitazoxanide was observed at 24 hours post-dose with a peak value of 3.4 ms (two-sided CI: 1.4, 5.4 ms). These findings demonstrate that neither a single dose of 675 mg nor 2,700 mg nitazoxanide prolonged the QT interval in healthy male and female volunteers. The safety results also demonstrate that all four treatments were well-tolerated and the most frequently reported adverse events in the nitazoxanide and moxifloxacin treatment groups were gastrointestinal disorders which were as expected according to the reference safety information., (© 2014, The American College of Clinical Pharmacology.)