The Cardiovascular Safety Profile of Renzapride,a Novel Treatment for Irritable Bowel Syndrome

Abstract

The cardiac safety of renzapride, a novel benzamide currently under clinical development for the treatment of irritable bowel syndrome, was investigated in a four-way randomized crossover electrocardiographic clinical study in healthy human subjects and also in an in vitro cardiac conductivity study in sheep isolated Purkinje fibres. The primary endpoint in the clinical study was prolongation of the individually corrected QT interval (QT_ci). No clinically or statistically significant prolongation of QT_ci after 4 or 20 mg renzapride compared with placebo was observed. The relative effects of renzapride and cisapride in the in vitro study showed that the cardiac action potential duration was unaltered by 0.2 and 2 μM renzapride, shortened by 20 μM renzapride, and prolonged by 1 μM cisapride. Cisparide was also a 1000-fold more potent inhibitor of human ether-a-go-go related gene (hERG) channels in HEK293 cells than renzapride. These studies indicate that therapeutic doses of renzapride are unlikely to prolong cardiac action potentials and, therefore, are also unlikely to cause cardiac arrhythmias in clinical use.