Effects of Lubiprostone, a Chloride Channel Activator, on Cardiac Parameters in Dogs

Abstract

Purpose: Treatment with lubiprostone, a type-2 chloride channel (ClC-2) activator used for the treatment of adults with chronic constipation, does not result in QTc prolongation in human subjects treated with supratherapeutic doses (up to 144 mcg) (Sprenger et al, Gastroenterology 132[4 Suppl 2]:A-325, 2007). Studies were performed to assess cardiac effects of lubiprostone in dogs. Methods: In an in vitro assay to evaluate lubiprostone effects on cardiac action potential, isolated canine Purkinje fiber preparations were exposed to increasing doses of lubiprostone (7.5, 75, and 750 pg/mL; 1.5–150 times the highest observed plasma concentration in humans) at 3 stimulus intervals, results of which were compared to time-matched vehicle control sequences. An in vivo study evaluated the effects of a single intraduodenally administered (ID) dose of lubiprostone (0, 10, 100, or 1000 mcg/kg) in male dogs. Blood pressure, heart rate, femoral artery blood flow, and electrocardiograms (ECGs) were collected at 7 time points over 2 hours post-dose. A second in vivo study evaluated the effects of repeated oral dosing of lubiprostone (up to 50 mcg/kg/day) in male and female dogs over a 39-week treatment period. ECGs were collected prior to dosing and at Weeks 13, 26, and 39. Results: The in vitro assay showed no remarkable changes in action potential duration or amplitude, resting membrane potential, or maximum rate of rise of the action potential at any of the concentrations tested. ID administration of lubiprostone had no effect on any cardiac parameter at any dose, with the exception of decreased mean blood pressure (34% maximum) between 10 and 120 minutes post-dose at 1000 mcg/kg, which is 1,250 times the recommended single dose in humans. Over 39 weeks of lubiprostone treatment at doses up to 50 mcg/kg/day (>31 times the recommended daily dose in humans) no abnormal changes in heart rate, QRS duration, QT interval, QTc, PR interval, or R wave were observed in male or female dogs. Conclusion:In vitro and in vivo testing of lubiprostone in dogs demonstrates a favorable cardiac profile at clinically relevant and supratherapeutic doses. This research was fully funded by Sucampo Pharmaceuticals, Inc.