Preclinical Electrophysiology Assays of Mitemcinal (Gm-611), a Novel Prokinetic Agent Derived From Erythromycin

Abstract

-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-gorelated gene (HERG) tail current in a concentration-dependent manner with IC 50 values of 20.2, 41.7, and 55.0 μM, 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 μM, 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.

Hemodynamic and Electrophysiological Effects of Mitemcinal (Gm-611), a Novel Prokinetic Agent Derived From Erythromycin in a Halothane-Anesthetized Canine Model

“…Therefore, direct assessment of the proarrhythmic risk of mitemcinal that prolongs the QT interval was conducted using an anesthetized proarrhythmic rabbit model. TdP was not evoked in this model even though the QT interval was observed from intravenous administration of mitemcinal (Kimura et al, 2007).…”

“…Mitemcinal inhibited the HERG current with an IC 50 of 20.2 μM and prolonged the MAP duration at a concentration of approximately 1.1 μM in anesthetized guinea pigs (Kimura et al, 2007). However, mitemcinal did not induce TdP in the anesthetized proarrhythmic rabbit model even when QT interval prolongation from intravenous administration of mitemcinal was observed (Kimura et al, 2007). In order to clarify the reason for these results, we investigated QT intervalprolonging effects in a halothane-anesthetized canine model and assessed hemodynamic and electrophysiological effects simultaneously.…”

“…Mitemcinal has shown potent gastrointestinal motility-stimulating activity via motilin receptors in rabbits, dogs and monkeys Ozaki et al, 2007;. Mitemcinal inhibited the human ether-a-gogo-related gene (HERG) current with an IC 50 of 20.2 μM and prolonged monophasic action potential (MAP) duration at a concentration of approximately 1.1 μM in anesthetized guinea pigs (Kimura et al, 2007). Contemporary preclinical in vitro and in vivo methods, however, have been imperfect in predicting druginduced tors ades de p ointes (Td P) in humans (Hoffmann and Warner, 2006).…”

Cardiovascular safety profile of MA-2029, a novel motilin receptor antagonist

“…MA-2029 did not increase the TRP at doses up to 21.1 μg/ml in dogs (n = 6) and showed no TdP at up to 4.63 μg/ml in rabbits (n = 6, data not shown for either study). On the other hand, cisapride caused a distinct increase in the TRP and induced TdP under the same test conditions (Kimura et al, 2007a(Kimura et al, , 2007b.…”