THE INFLUENCE OF CISAPRIDE AND CLARITHROMYCIN ON QT INTERVALS IN HEALTHY-VOLUNTEERS

Objective: Recently a few cases of long QT syndrome were reported duri ng treatment with cisapride, In most of these cases, risk factors for cardiac arrhythmias or pharmacologic interactions might have been invo lved, and the role of cisapride remained unclear, Macrolides such as c larithromycin potentially interact with the metabolic elimination of c isapride and have overlapping indication areas. We therefore studied w hether combined treatment with clarithromycin and cisapride leads to p harmacokinetic changes and increased QT intervals. Methods: The study was an open, randomized, 2-way crossover study with washout periods of 1 week. Twelve healthy volunteers were recruited. Treatments were cis apride (10 mg 4 times a day) for 10 days with concomitant clarithromyc in (500 mg twice a day) from days 6 through 10, or clarithromycin (500 mg twice a day) for 10 days combined with cisapride (10 mg times a da y) from days 6 through 10, Frequent ECG recordings were performed for 24 hours before drug treatment (baseline), After 5 days of monotherapy and combination therapy, frequent ECG recordings and assessments of p lasma drug levels were performed for 24 hours, Results: Clarithromycin alone was associated with a minimal increase in QTc intervals, Monoth erapy with 10 mg cisapride 4 times a day led to a concentration-depend ent QTc elevation, amounting to 6 ms during steady state. Combination of cisapride and clarithromycin caused an average QTc increase of 25 m s above pretreatment values and 3-fold increases in cisapride concentr ations. Conclusions: QTc elevations after cisapride or clarithromycin alone remained within the normal range of diurnal variation, Coadminis tration of cisapride and clarithromycin produced a substantial QT prol ongation. The data support the recently purported interaction between cisapride and clarithromycin and thus the filed contraindication to co mbine these drugs.