Characterization of microminipigs as an in vivo experimental model for cardiac safety pharmacology

We pharmacologically characterized microminipigs as an in vivo experimental model by assessing cardiovascular effects of pilsicainide,verapamil and e-4031,which can preferentially inhibit cardiac na+,ca2+ and k+ channels,respectively. intravenous infusion of 1 mg/kg of pilsicainide (n = 4),0.1 mg/kg of verapamil (n = 4) and 0.01 followed by 0.1 mg/kg of e-4031 (n = 5) over 10 min decreased the heart rate,mean blood pressure and ventricular contractility. moreover,pilsicainide prolonged the pr interval,qrs width and qtc; verapamil prolonged the pr interval,but shortened the qrs width and qtc; and e-4031 prolonged the qtc,whereas no substantial change was detected in the pr interval or qrs width. peak plasma concentrations of pilsicainide,verapamil and e-4031 in microminipigs were 1.7–4.8 times higher than those expected in humans and dogs,possibly due to smaller effective volume of drug distribution. the extent of the drug-induced cardiovascular responses was generally greater in microminipigs than in humans and dogs,which could be explained by the following possibilities; namely unique pharmacokinetic profile,less great reflex-mediated increase of sympathetic tone and/or smaller repolarization reserve in microminipigs. these information may make it feasible to apply this new-type animal to a tool for assessing cardiac safety profiles of new chemical entities. © 2017 the authors