No cardiac effects of therapeutic and supratherapeutic doses of rupatadine: Results from a 'thorough QT/QTc study' performed according to ICH guidelines

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Drug-induced prolongation of QTc interval on the ECG increases the risk of ventricular tachyarrhythmias. • This problem beset the antihistamine class of drugs in the 1990s and resulted in the withdrawal of two drugs, terfenadine and astemizole. • In 2005 the International Conference on Harmonization approved guideline E14, which has been termed a 'thorough QT/QTc study', for the routine clinical testing of the proarrhythmic potential of pharmacotherapy. WHAT THIS PAPER ADDS • To our knowledge, this is one of the first published trials to evaluate multiple doses of antihistamine therapy using the new criteria and it confirms the cardiac safety of rupatadine, an anti-H1 compound with activity on platelet-activating factor. AIMS: To evaluate the effects of therapeutic and supratherapeutic doses of rupatadine on cardiac repolarization in line with a 'thorough QT/QTc study' protocol performed according to International Conference on Harmonization guidelines. METHODS: This was a randomized (gender-balanced), parallel-group study involving 160 healthy volunteers. Rupatadine, 10 and 100 mg day-1, and placebo were administered single-blind for 5 days, whilst moxifloxacin 400 mg day-1 was given on days 1 and 5 in open-label fashion. ECGs were recorded over a 23-h period by continuous Holter monitoring at baseline and on treatment days 1 and 5. Three 10-s ECG samples were downloaded at regular intervals and were analysed independently. The primary analysis of QTc was based on individually corrected QT (QTcI). Treatment effects on QTcI were assessed using the largest time-matched mean difference between the drug and placebo (baseline-subtracted) for the QTcI interval. A negative 'thorough QT/QTc study' is one where the main variable is around ≤5 ms, with a one-sided 95% confidence interval that excludes an effect >10 ms. RESULTS: The validity of the trial was confirmed by the fact that the moxifloxacin-positive control group produced the expected change in QTcI duration (around 5 ms). The ECG data for rupatadine at both 10 and 100 mg showed no signal effects on the ECG, after neither single nor repeated administration. Furthermore, no pharmacokinetic/pharmacodynamic relationship, gender effects or clinically relevant changes in ECG waveform outliers were observed. No deaths or serious or unexpected adverse events were reported. CONCLUSIONS: This 'thorough QT/QTc study' confirmed previous experience with rupatadine and demonstrated that it had no proarrhythmic potential and raised no concerns regarding its cardiac safety. © 2010 The Authors.