mitemcinal and Long-QT-Syndrome

Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. Erythromycin has shown QT prolongation and torsades de pointes (TdP) in humans and cisapride, a second class of prokinetic agents typified by the 5-HT(4) receptor agonist, has been terminated due to TdP. In this study an extended series of safety pharmacology protocols and evaluations have been undertaken to assess the potential risk of mitemcinal on QT prolongation or proarrhythmic effects. Mitemcinal and its metabolites, GM-577 and GM-625, inhibited the human ether-a-go-go-related gene (HERG) tail current in a concentration-dependent manner with IC(50) values of 20.2, 41.7, and 55.0 microM, respectively. Administration of 10 mg/kg mitemcinal in anesthetized guinea pigs resulted in a slight prolongation of the monophasic action potential (MAP) duration during atrial pacing at the plasma concentration of mitemcinal 1.1 microM, with low maximum increases in MAPD(70) (6.6%) and MAPD(90) (4.6%) relative to vehicle. A 10-min infusion of 20 mg/kg of mitemcinal in a proarrhythmic rabbit model did not evoke TdP even when QT and corrected QT (QTc) intervals were significantly prolonged. In this study, the Cmax plasma-free concentration of mitemcinal indicates that the prolongation was more than 400-fold that of the therapeutic dose. Our findings of a wide safety margin and the absence of TdP within this margin suggest that mitemcinal may provide sufficient safety in clinical use.

Topics: Action Potentials; Animals; Cell Line; Cisapride; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Electrocardiography; ERG1 Potassium Channel; Erythromycin; Ether-A-Go-Go Potassium Channels; Gastrointestinal Agents; Gastrointestinal Motility; Guinea Pigs; Heart Atria; Heart Conduction System; Heart Rate; Humans; Long QT Syndrome; Male; Potassium Channel Blockers; Rabbits; Risk Assessment; Time Factors; Torsades de Pointes; Transfection

Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. We investigated the QT-prolonging effects of mitemcinal using a halothane-anesthetized canine model. Intravenous administration of mitemcinal at doses of more than 8.3 mg/kg per 10 min significantly prolonged the QT interval corrected by Fridericia's corrections. Mitemcinal exhibited a bradycardiac effect and produced significantly greater prolongation in monophasic action potential duration (MAP(90)) at sinus rhythm compared with MAP(90) at pacing and showed reverse use-dependent prolongation of repolarization, suggesting that the negative chronotropic effect of mitemcinal potentiates the prolongation of the repolarization period. A technique using MAP/pacing electrodes allowed measurements of both MAP(90) and effective refractory period (ERP) simultaneously at the same ventricular site. Although mitemcinal slightly prolonged the MAP(90(CL400)) and ERP in comparison with the control group at the dose of 25 mg/kg per 10 min, the terminal repolarization period, the difference between MAP(90(CL400)) and ERP, did not increase suggesting the absence of a proarrhythmic effect even with a 7000-fold for the therapeutic blood concentration as free level. The electrophysiological results from mitemcinal in this study indicate that the risk of serious arrhythmia such as torsades de pointes, a major clinical concern related to QT interval prolongation, might be low.

Topics: Action Potentials; Anesthesia, General; Anesthetics, Inhalation; Animals; Blood Pressure; Cardiac Pacing, Artificial; Cisapride; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Erythromycin; Gastrointestinal Agents; Gastrointestinal Motility; Halothane; Heart Rate; Infusions, Intravenous; Long QT Syndrome; Male; Models, Animal; Risk Assessment; Time Factors; Torsades de Pointes; Ventricular Function, Left; Ventricular Pressure