Preclinical electrophysiology assays of mitemcinal (GM-611), a novel prokinetic agent derived from erythromycin.
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.
Kimura
Kazuya
K
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. kimurakzy@chugai-pharm.co.jp
Tabo
Mitsuyasu
M
Itoh
Misae
M
Mizoguchi
Keiji
K
Kato
Atsuhiko
A
Suzuki
Masami
M
Itoh
Zen
Z
Omura
Satoshi
S
Takanashi
Hisanori
H
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D020117:Cisapride / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000097:blood / Q000633:toxicity*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D026902:Potassium Channel Blockers / Q000097:blood / Q000633:toxicity*; D011817:Rabbits; D018570:Risk Assessment; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced*; D014162:Transfection