Cardiac Safety of Rupatadine in a Single‐Ascending‐Dose and Multiple‐Ascending‐Dose Study in Healthy Japanese Subjects, Using Intensive Electrocardiogram Assessments—Comparison With the Previous White Caucasian Thorough QT Study

Abstract

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. Keywords rupatadine, Japanese, cardiac safety, food effect, assay sensitivityThe International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline E14 recommends that the QTprolonging potential of a drug be evaluated primarily by a specific "thorough QT" (TQT) study. 1 In 2005, when the ICH was first adopted, it was not expected that the results of a TQT would be influenced by ethnic factors. However, emerging clinical experience has suggested that interethnic differences can be of particular relevance when assessing the safety of some drugs. 2 Since 2010, when the ICH E14 was fully adopted in Japan, the suitability of foreign data to provide proarrhythmic liability information concerning the Japanese population is still under assessment. Nevertheless, more efficient approaches to reduce the associated costs and alternatives to a conventional TQT study have been extensively discussed to modify the current regulatory requirements now allowing thorough QT assessments in other trials.

Cardiac safety of second‐generation H1‐antihistamines when updosed in chronic spontaneous urticaria

“…An ICH-compliant TQT study showed that rupatadine at a dose of 100 mg, tenfold higher than the recommended dose, did not induce significant changes in cardiac repolarization neither when given as a single dose nor when administered once a day for 5 days. 19 Similar results have recently been reported in Japanese volunteers by Taubel et al 96 In conclusion, rupatadine updosing does not seem to increase the length of cardiac repolarization to any extent.…”

“…As previously reported also, the hERG IC 50 of desloratadine, the major metabolite generated by rupatadine in vivo, is in the μM range. After oral administration of single or of repeated (five days) standard 10 mg dose doses, rupatadine C max was always about 2000‐fold lower than the aforementioned average IC 50 for hERG blockade (Table ) . Church and colleagues showed that after a single dose of 40 mg (fourfold higher than the recommended dose), rupatadine C max was 36.38 nM, whereas Taubel et al .…”

“…After oral administration of single or of repeated (five days) standard 10 mg dose doses, rupatadine C max was always about 2000-fold lower than the aforementioned average IC 50 for hERG blockade (Table 1). 95,96 Church and colleagues 2 showed that after a single dose of 40 mg (fourfold higher than the recommended dose), rupatadine C max was 36.38 nM, whereas Taubel et al 96 found values of 38.5 and 552.9 nM in Caucasian subjects receiving 100 mg rupatadine (ten times the recommended dose) as a single or as repeated doses, respectively. An ICH-compliant TQT study showed that rupatadine at a dose of 100 mg, tenfold higher than the recommended dose, did not induce significant changes in cardiac repolarization neither when given as a single dose nor when administered once a day for 5 days.…”

Histamine, histamine receptors, and anti-histamines in the context of allergic responses

“…No major sedating effect was described (Shamizadeh et al 2014;Potter et al 2016). Rupatadine has no or low side effect potential on cardiac repolarization (De Bruin et al 2002;Yap and Camm 2002;Täubel et al 2018); however, careful surveillance and risk-minimalization is required in patients in patients with a history of QTc prolongation and (or) torsade de pointes, including congenital long QT syndromes, or a history of other cardiac arrhythmias. There has been 1 torsade de pointes reported (Fité-Mora 2009) with rupatadine during post-market use, thus it should not be recommended to be used Rupatadine should not be administered concomitantly with erythromycin, ketoconazole or grapefruit.…”

Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

“…Use of the exposure-response approach is expected to be challenging and/or erroneous in many situations, including, but not limited to, the following: Additional references are provided. [51][52][53][54][55][56][57][58]…”