ANTIARRHYTHMIC AND ELECTROPHYSIOLOGIC EFFECTS OF SUBLINGUAL IBUTILIDEFUMARATE

Ibutilide fumarate is a class III antiarrhythmic agent in phase Ill cl inical trials. Due to rapid hepatic metabolism, ibutilide has a low or al bioavailability (< 10%). To assess alternate routes of administrati on, we performed repeated studies of the electrophysiologic effects of sublingual ibutilide (0.03, 0.1, and 0.3 mg/kg; 0.07, 0.2, and 0.7 mu mol/kg) in pentobarbital anesthetized dogs. Peak significant increase s in QTc interval, ventricular effective refractory period (VERP), and right ventricular monophasic action potential duration (MAPD90) were achieved 30 min following 0.1 or 0.3 mg/kg (0.2 and 0.7 mu mol/kg) ibu tilide and were coincident with peak plasma ibutilide levels. The dura tion of significant effects ranged from 2 to 5 h. Peak effects were: Q Tc + 121 msec, MAPD90 +71 msec, and VERP +53 msec. The 0.3 mg/kg (0.7 mu mol) dose significantly decreased heart rate 10 min post dosage thr ough 5 h. The 0.03 mg/kg (0.07 mu mol) dose increased MAPD90 at 1 to 2 h but was otherwise ineffective. The plasma half life of ibutilide wa s 2.8 h, with a 72% bioavailability relative to an equivalent intraven ous dose. Based on the electrophysiologic results, we chose to test th e 0.1 mg/kg (0.2 mu mol) sublingual ibutilide dose for termination of sustained atrial flutter in anesthetized dogs with y-shaped right atri al incisions. The administration of 0.1 mg/kg (0.2 mu mol) sublingual ibutilide during sustained atrial flutter resulted in termination of a trial flutter in all cases (n = 4) after a mean time interval of 11.4 +/- 0.8 min. Termination of atrial flutter was associated with ibutili de plasma levels of 19.6 +/- 6.3 ng/ml, and 30 and 18 msec increases i n atrial and ventricular effective refractory periods. Atrial flutter could be reinduced in 2 dogs, one at 3 h and one at 4 h post ibutilide administration. The ability to reinduce atrial flutter was associated with a reduction in ibutilide plasma levers to 2.3 +/- 0.7 ng/ml. We conclude that sublingual ibutilide is rapidly absorbed and produces si gnificant electrophysiologic and antiarrhythmic effects, and is a pote ntial alternative to intravenous and oral therapy. (C) 1995 Wiley-Liss , Inc.