Assessment of the cardiac safety of prucalopride in healthy volunteers: a randomized, double‐blind, placebo‐ and positive‐controlled thorough QT study

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Drugs interacting with the hERG potassium channel are associated with a prolongation of the QT interval, which can lead to life‐threatening arrhythmias such as torsades de pointes. • Early prokinetic agents, such as cisapride, display poor selectivity for their target receptor, 5‐HT 4 , also interacting with hERG channels and, as a consequence, have a poor safety and benefit/risk profile. • Prucalopride, a novel and selective 5‐HT 4 agonist with enterokinetic activity, is indicated for the treatment of chronic constipation in adults in whom laxatives fail to provide adequate relief. WHAT THIS STUDY ADDS • This study describes the results of a novel thorough QT study design involving a parallel group with nested crossover for positive control. • The mean QT c interval was not prolonged in patients receiving therapeutic (2 mg) or supra‐therapeutic (10 mg) doses of prucalopride, as assessed using QT c SS. • New generation prokinetic agents with improved selectivity for 5‐HT 4 receptors, such as prucalopride, should help improve the benefit/risk profile of these agents and, ultimately, their clinical usefulness. AIMS To assess steady‐state effects of therapeutic and supra‐therapeutic doses of prucalopride on the QT interval using a novel design involving a parallel placebo group with nested crossover for positive control. METHODS A double‐blind, double‐dummy, placebo‐ and active‐controlled study was conducted in 120 healthy male and female volunteers (NCT00903747). Volunteers were randomized to receive prucalopride 2–10 mg once daily (therapeutic and supratherapeutic doses, respectively) (group 1), placebo with 400 mg moxifloxacin on day 1 (group 2a), or placebo with moxifloxacin on day 15 (group 2b). Twelve‐lead 24 h Holter ECGs recorded at various time‐points were evaluated blind and centrally. RESULTS Estimated mean difference in study specific corrected QT interval (QT c SS) time‐matched change from baseline between prucalopride (2 and 10 mg) and placebo was <5 ms at all time points (maximum mean difference: 3.83 ms at 3.5 h post dose on day 5 with 2 mg [90% Cl −0.33, 6.38 ms]). Upper limits of the two‐sided 90% CI for QT c SS were all <10 ms. There were no outlying QT c SS values >450 ms and no subjects had an increase >60 ms following prucalopride. Moxifloxacin produced the expected significant changes in QT c SS (>5 ms, maximum of +12.7 ms at 5 h post dose) at all time‐points except 1 h post dose. Prucalopride resulted in small increases in heart rate (maximum of 5.8 beats min –1 ), which were similar for 2 and 10 mg. Prucalopride was well tolerated after first day of treatment. CONCLUSION Prucalopride at both therapeutic and supra therapeutic doses has no clinically significant effects on cardiac repolarisation in healthy volunteers.